Systems and methods related to microfluidic devices (e.g., microfluidic devices comprising layers of films) are generally described.
Passive microfluidic platforms, such as lateral flow assays (LFAs), are commonly used for point of care diagnostics due to their low cost and simplistic microfluidic capabilities. LFAs, however, have limited microfluidic capabilities and cannot be used for performing advanced microfluidic operations (e.g., mixing and diluting liquids, delivering different liquid samples and/or reagents sequentially, stopping liquid flow for incubation and restarting the flow for sensing, etc.). For this reason, active microfluidic systems with multiple bulky pumps, actuators, controllers, mechanical valves, and/or power sources are required to perform these advanced microfluidic operations. Capillary microfluidic systems offer advantages that LFAs do not provide, since the aforementioned advanced microfluidic operations can be accomplished using capillary action. Conventional microfluidic devices with capillary functions require specifically designed geometries and are therefore produced by advanced fabrication techniques using expensive equipment.
Systems and methods related to microfluidic devices (e.g., microfluidic devices comprising layers of films) are generally described. The subject matter of the present disclosure involves, in some cases, interrelated products, alternative solutions to a particular problem, and/or a plurality of different uses of one or more systems and/or articles.
According to some embodiments, a microfluidic device is described, the microfluidic device comprising a substrate configured to facilitate fluid transport; one or more intermediate layers disposed on the substrate, wherein the one or more intermediate layers are configured to define a plurality of fluidly connected microfluidic components; and a top layer disposed on the one or more intermediate layers.
In certain embodiments, a method of manufacturing a microfluidic device is described, the method comprising applying one or more intermediate layers to a substrate to define a plurality of fluidly connected microfluidic components; and applying a top layer to a topmost one of the one or more intermediate layers.
According to certain embodiments, a microfluidic device is described, the microfluidic device comprising a plurality of microfluidic channels, wherein at least a portion of at least one microfluidic channel has a transverse cross-section that is orthogonal to a direction of flow through the at least one microfluidic channel, and wherein a first portion of the transverse cross-section has a first hydrophobicity or hydrophilicity and a second portion of the transverse cross-section has a second hydrophobicity or hydrophilicity that is different than the first hydrophobicity or hydrophilicity.
According to some embodiments, a microfluidic device is described, the microfluidic device comprising a substrate configured to facilitate fluid transport; one or more intermediate layers disposed on the substrate, wherein the one or more intermediate layers are configured to at least partially define a plurality of microfluidic channels; and a top layer disposed on the one or more intermediate layers, wherein a bottom surface of at least a portion of at least one microfluidic channel has a first hydrophilicity or hydrophobicity and one or more side walls of at least a portion of the at least one microfluidic channel has a second hydrophilicity or hydrophobicity that is greater than the first hydrophilicity or hydrophobicity.
In certain embodiments, a microfluidic device is described, the microfluidic device comprising a substrate configured to facilitate fluid transport; an intermediate layer disposed on the substrate, wherein the intermediate layer is configured to at least partially define a first microfluidic channel and a second microfluidic that intersect with each other; and a top layer disposed on the one or more intermediate layers, wherein an interface between the first microfluidic channel and the second microfluidic channel is patterned such that the interface is configured to function as a stop valve.
According to some embodiments, a microfluidic device is described, the microfluidic device comprising a substrate configured to facilitate fluid transport; one or more intermediate layers disposed on the substrate, wherein the one or more intermediate layers are configured to at least partially define a microfluidic channel; and a hydrophobic layer disposed on the one or more intermediate layers, wherein the hydrophobic layer is more hydrophobic than the intermediate layers, and wherein a portion of the hydrophobic layer exposed to an interior of a portion of the microfluidic channel has a first transverse dimension at an upstream location and a second transverse dimension at a downstream location, wherein the first transverse dimension is smaller than the second transverse dimension such that the portion of the microfluidic channel is configured to act as a retention valve.
Some embodiments are related to a microfluidic device comprising a channel including a first portion extending along a length of the channel; a second portion extending along the length of the channel; and a third portion extending along the length of the channel wherein the third portion is disposed between the first portion of the channel and the second portion of the channel, and wherein the third portion is configured to isolate the first portion of the channel from the second portion of the channel until a liquid is flowed through the third portion of the channel.
Some embodiments are related to a microfluidic device comprising a substrate; a first intermediate film layer disposed on the substrate, wherein a recessed channel is formed in the first intermediate film layer; and a second intermediate film layer disposed on the first intermediate film layer, wherein a primary channel is formed in the second intermediate film layer, and wherein a first portion of the primary channel is disposed on a first side of the recessed channel and a second portion of the primary channel is disposed on a second side of the recessed channel opposite from the first side.
Some embodiments are related to a method of operating a microfluidic device. In certain embodiments, the method comprises flowing a first liquid through a recessed channel disposed between a first portion of a primary channel and a second portion of a primary channel; and mixing a first substance in the first portion of the primary channel with a second substance in the second portion of the primary channel after the fluid is flowed through the recessed channel.
In some embodiments, a microfluidic device comprises a first layer, a second layer disposed on the first layer, and a third layer disposed on to the second layer, wherein a portion of the third layer is directly disposed on the first layer, and wherein the portion of the third layer forms at least a portion of a microfluidic channel.
In some embodiments, a microfluidic device comprises a microfluidic channel extending in a first direction, the microfluidic channel comprising a first portion and a second portion, wherein the second portion is spaced from the first portion in a second direction transverse to the first direction, wherein a surface of the microfluidic channel includes an inclined portion between the first and second portions, wherein a height of the first portion is less than a height of the second portion, and wherein the heights of the first and second portions extend in a third direction perpendicular to both the first and second directions.
In some embodiments, a method comprises introducing fluid into a first portion of a microfluidic channel, the microfluidic channel extending in a first direction; flowing the fluid in a second direction transverse to the first direction from the first portion of the microfluidic channel to a second portion of the microfluidic channel, wherein the first portion of the microfluidic channel and the second portion of the microfluidic channel are at least partially coextensive along a length of the microfluidic channel; and flowing the fluid out of the second portion of the microfluidic channel to an outlet of the microfluidic channel, the outlet spaced from the first portion in the first direction.
Other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and/or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and/or inconsistent disclosure with respect to each other, then the document having the later effective date shall control.
Non-limiting embodiments of the present disclosure will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment shown where illustration is not necessary to allow those of ordinary skill in the art to understand. In the figures:
Systems and methods related to microfluidic devices (e.g., microfluidic devices comprising layers of films) are generally described.
Passive capillary action-driven microfluidic systems offer advantages that lateral flow assays (LFAs) and active microfluidic systems do not provide, because advanced microfluidic operations can be accomplished using surface tension forces associated with capillary action to drive multiple functions. A variety of passive capillary elements may be used to perform these advanced microfluidic operations successfully. Conventional capillary microfluidic devices without active components require specifically designed geometries and/or additional surface treatments to create multiple functional capillary elements. These passive capillary elements perform different functions during loading and running the microfluidic device, which increases their design complexity to be able to perform the required advanced operations without using active elements. For example, the passive capillary elements may have small feature sizes (e.g., 10-1,500 microns), and they need to be designed with certain surface properties and specific geometries to be able to control the capillary pressure precisely. Microfluidic devices with advanced functionalities based on capillary action therefore require specifically designed geometries, and such devices are produced by advanced fabrication techniques that require expensive equipment.
Furthermore, certain fabrication techniques that are currently employed use materials that need additional surface treatment steps (e.g., plasma treatment, salinization) to tailor contact angles and control the capillary pressure at specific locations within the microfluidic device. This surface treatment, however, must be stable when long storage times are needed during product development. Moreover, current conventional surface treatment procedures cannot control the surface treatment location on the microfluidic device, as all surfaces of the device are exposed evenly to the surface treatment modifications.
To this end, the Inventors have recognized and appreciated that there is a desire for lower cost and technically easier methods for fabricating microfluidic devices driven by passive capillary action while maintaining the ability to perform advanced microfluidic operations by imparting different functionalities to different portions of the microfluidic device.
Described herein are new designs, materials, and methods for fabrication of passive capillary elements that can precisely modify and control the capillary pressure at different sections of a microfluidic device. The Inventors have recognized and appreciated that the capillary pressure can be controlled by: (i) the contact angle on hydrophilic and hydrophobic surfaces; and (ii) the geometry of the passive capillary elements. According to some embodiments, these passive elements may perform advanced microfluidic operations such as sequential liquid delivery steps, hydrating dried reagents, and mixing and diluting liquids, with stable surface properties and without costly surface modification techniques.
According to some embodiments, microfluidic devices that comprise one or more patterned films where each film has at least a portion of a profile of a desired portion of the microfluidic device formed in the one or more patterned films are described herein. The one or more patterned films are stacked together (e.g., bonded) to form the microfluidic device. In certain embodiments, for example, the microfluidic device comprises: a substrate; one or more patterned intermediate layers that define a plurality of passive elements (e.g., channels, valves, reservoirs, other microfluidic components); and a top layer to cover the microfluidic device. In some embodiments, the substrate is configured to facilitate fluid flow through one or more microfluidic channels of the microfluidic device. The one or more intermediate layers, in some embodiments, each comprise a film (e.g., a polymer film) that may have either the same or varying degrees of hydrophobicity and/or hydrophilicity. In either case, a top layer may be applied over the last intermediate layer. The microfluidic devices described herein advantageously comprise functional passive elements configured to perform advanced capillary microfluidic operations without using active pumps, valves, or power sources.
The disclosed microfluidic devices may be fabricated by applying the one or more intermediate layers over the substrate such that the first intermediate layer binds (e.g., adheres) to the substrate and/or another intermediate layer. Depending on the embodiment, the one or more intermediate layers may include an adhesive material applied to one or both opposing sides of the film layers to bond each layer to an adjacent layer and/or the substrate. For example, in some embodiments, a pressure sensitive adhesive may be used. However, embodiments in which the films of a microfluidic device are assembled without the use of adhesives are also contemplated. For instance, in some embodiments, the film layers may be bonded to one another using appropriate lamination techniques and/or any other appropriate bonding method as the disclosure is not so limited. Specific bonding techniques are described in further detail below.
The use of individual layers to form the different portions of the microfluidic components may enable the use of different materials for various portions of a microfluidic device, which facilitates the fabrication of devices with tailored surface properties. For instance, the hydrophobicity and/or hydrophilicity of the different layers may vary from layer to layer, or the hydrophobicity and/or hydrophilicity may vary within the same layer. Thus, a device may be configured such that different variations and combinations of hydrophobic and hydrophilic materials may be used to form the substrate, the one or more intermediate layers, and/or the top layer of a microfluidic device. In addition, the thickness of one or more layers, their geometries, and/or their dimensions may be tailored such that the one or more layers contribute to controlling capillary pressures throughout the device. Such a configuration advantageously enables the fabrication of microfluidic devices that can be fine-tuned to perform advanced microfluidic operations, including sequential delivery and/or mixing of liquid samples and/or reagents, timed and/or stepped operations using sacrificial reservoirs that can act as timers, stopping and incubating liquid samples, and starting and stopping flow through a device using sacrificial reservoirs, by precisely controlling the capillary pressures at desired locations within the device. Furthermore, the fabrication methods described herein that provide the ability to fine-tune the hydrophilicity and/or hydrophobicity of the one or more layers of the device may eliminate the need for additional surface treatments, resulting in devices with longer shelf lives and less expensive production costs.
As described above, the microfluidic devices described herein may comprise a plurality of connected microfluidic components, such as channels, valves, and/or reservoirs. In some embodiments, for example, one or more layers of the microfluidic device may define one or more microfluidic channels. One or more properties (e.g., surface properties, physical properties) of at least a portion of a microfluidic channel may be tailored such that the portion of the microfluidic channel is configured to act as a valve (e.g., a stop valve, a retention valve). As explained in greater detail herein, for example, the hydrophobicity or hydrophilicity of a portion of a channel may be modified relative to other components of or the remainder of the channel, such that the modified portion is configured to act as a stop valve. In other embodiments, the geometry of a portion of channel may be constructed such that the portion of the channel is configured to act as a retention valve.
Stop valves are configured to stop the flow of liquid at specific positions within the microfluidic device. Conventional techniques used to fabricate stop valves involve surface treatment methods in which the channel surfaces are rendered hydrophilic or hydrophobic. Low surface tension liquids in such conventional microfluidic devices, however, may leak from upper channels to lower channels resulting in leakage through the stop valve. Described herein are two-stepped and single-layer capillary stop valves formed from hydrophilic and hydrophobic materials that advantageously enable the ability to work with low surface tension liquid samples and reagents.
According to some embodiments, a microfluidic channel may be defined by more than one layer of the microfluidic device (e.g., a substrate and/or one or more intermediate layers, one or more intermediate layers) such that the hydrophobicity varies within the same channel. In some embodiments, for example, a microfluidic channel may have a transverse cross-section that is orthogonal to a direction of flow through the microfluidic channel, wherein a first portion of the transverse cross-section has a first hydrophobicity and a second portion of the transverse cross-section has a second hydrophobicity that is different from the first hydrophobicity. Configuring the microfluidic channel in this way advantageously provides a stop valve in which a fluid may flow along a comparatively less hydrophobic portion of the channel and stop at the comparatively more hydrophobic portion of the channel.
In certain embodiments, a microfluidic channel may be defined by more than one layer of the device (e.g., a substrate and/or one or more intermediate layers, one or more intermediate layers) such that the surfaces and/or side walls of the microfluidic channel vary in hydrophobicity relative to one or more adjacent layers. In some embodiments, for example, the bottom surface of a microfluidic channel may be defined by a substrate or a first intermediate layer, and may be rendered hydrophilic, and the side walls of the microfluidic channel may be defined by one or more intermediate layers, and may be rendered hydrophobic or less hydrophilic than the bottom surface. In some such embodiments, the configuration of the microfluidic device advantageously allows the side walls of the microfluidic channel to stop low surface tension liquids from leaking and breaking the stop valve.
According to some embodiments, the surface properties of a single intermediate layer may be selectively modified to fabricate a stop valve. For example, a portion of a microfluidic channel defined by an intermediate layer may be patterned to change the degree of hydrophilicity or hydrophobicity of the surface of the portion relative to an adjacent portion of the microfluidic channel and provide spatial wettability inside the channel. The single layer stop valve can advantageously be used to stop the flow in one channel and trigger flow from another channel on the same intermediate layer, which can be done by defining patterns (e.g., by laser etching and/or engraving) in the microfluidic channel to enable the merging of two liquids effectively at intersecting channels. As explained in greater detail herein, various patterns, such as a triangular pattern, may be used to stop and restart the flow and merge liquids.
Other mechanisms of controlling the capillary pressure in the microfluidic channels, besides tuning the hydrophobicity and/or hydrophilicity of the channels, include changing the geometry and/or dimensions of the channel to facilitate capillary action. In some embodiments, for example, the geometry of a hydrophobic or hydrophilic portion of a microfluidic channel may be configured such that the hydrophobic or hydrophilic portion of the channel acts as a valve (e.g., a stop valve, a retention valve). A portion of the microfluidic channel may be fluidly connected to a liquid reservoir, and the hydrophobic portion of the microfluidic channel may include a first geometry with a first transverse dimension (e.g., a width perpendicular to a longitudinal axis of the channel, a depth perpendicular to a longitudinal axis of the channel) that transitions into a second narrower geometry with a second smaller transverse dimension. The change in the width and/or depth of the microfluidic channel may permit the portion of the microfluidic channel to act as a retention valve due to the increased capillary pressure at the section of the microfluidic channel with the smaller transverse dimension. One way in which to provide such a construction is a hydrophobic layer with a cut out with a narrower upstream geometry and a wider downstream geometry as elaborated on further below. In one specific embodiment, a suitable geometry may include, for example, a triangular geometry, wherein the narrow portion of the triangular geometry is upstream, proximate to a liquid reservoir, and the wide portion of the triangular geometry is downstream.
Some portions and/or sections of the microfluidic device have dual functions when operating the device. An inlet reservoir, for example, should enable facile filling during loading the device and may act as a retention valve to pin the liquid during running the device. In some embodiments, the geometry at one or more inlet reservoirs may enable liquid flow when filling the device, while a comparatively more narrow section of the reservoir inlet acts as a retention valve when running the device.
Some embodiments described herein are related to a microfluidic channel having a gap or area of increased hydrophobicity in between two separated portions of the channel to separately pin one or more liquids in one or more desired portions of the channel. In some embodiments, for example, a channel has a middle portion disposed between two opposing portions of the channel extending along a length of the channel. The middle portion may isolate liquids separately contained in one or both of the opposing portions of the channel, which may also be referred to as the two flanking portions of the channel. The isolation may be provided by a capillary stop valve effect, for example by making at least one surface of the middle portion more hydrophobic than adjacent surfaces of the two flanking portions. A liquid may be added in the middle portion such that liquids in the two flanking portions are intermixed by forming one single liquid block inside the channel. The intermixing may be used to perform intermixing of different liquids separately isolated on the flanking portions, or be used to reconstitute one or more dried reagents held in one or both flanking portions of the channel.
In some embodiments, the middle portion of a channel is a recessed portion disposed on a substrate or an intermediate layer, and having two side walls adjacent to the respective flanking portions of the channel. Isolation may be formed by making at least one of the bottom surfaces or side walls of the recessed portion more hydrophobic than adjacent surfaces of the flanking portions of the channel.
In some embodiments, the channel having a gap or area of increased hydrophobicity in between two separated portions of the channel may be constructed from patterned layers of hydrophilic and hydrophobic films and polymers. These layers are designed to precisely modify and control the capillary pressure at different sections for fabricating various functional capillary elements without using active pumps, valves, and/or power sources. This method enables fabrication of structures with different surface properties, providing precise control over capillary pressures at desired locations. The structures also can have different surface properties on the same layer by modifying the hydrophilicity or hydrophobicity of the surface in defined patterns to provide spatial wettability. The top and/or the bottom surface of the layers may, in some embodiments, be treated with a hydrophobic or hydrophilic coating to control the capillary pressure. The thickness of the layers and their geometries may contribute to controlling the capillary pressure and varying the capillary pressure at different locations. Different fabrication and cutting methods of the layers can affect the surface properties on the side walls of the layers, which may result, for example, in increased differences in hydrophobic properties of different portions of the channel. Accordingly, the capillary pressure can be also tuned by choosing the fabrication and cutting method. For example, stronger isolation between portions of the channel may be created due to increased differences in hydrophobicity. Combining layers with different surface properties and patterned surface treatment enables fabrication of capillary structures with more robust functionalities to work with virtually all liquids, samples, and reagents, even those with low surface tensions.
In certain embodiments, a microfluidic channel may be defined by more than one layer of the microfluidic device (e.g., a substrate and/or one or more intermediate layers, one or more intermediate layers) such that the channel geometry (e.g., channel height, channel inclination angle) varies within the same channel. In some embodiments, for example, a microfluidic channel may have a transverse cross-section that is orthogonal to a direction of flow through the microfluidic channel, wherein a first portion of the transverse cross-section has a first channel height, and a second portion of the transverse cross-section has a second channel height that is different from the first channel height. Configuring the microfluidic channel in this way may advantageously provide a capillary pressure gradient in which a fluid may flow from a portion of the channel with comparatively high capillary pressure toward a portion of the channel with comparatively low capillary pressure. Accordingly, the geometry of a microfluidic channel may be designed to encourage fluid flow in a direction transverse to a length of the microfluidic channel.
According to some embodiments, for example, described herein are microfluidic devices that comprise microfluidic channels with inclined surfaces, such that different portions of the microfluidic channel are associated with different channel heights. By tailoring the height of the microfluidic channel in different portions of the channel, different capillary pressure in different portions of the channel may be provided. Accordingly, certain flow properties of a fluid within the microfluidic channel may be controlled by designing the geometry of the microfluidic channel appropriately. A microfluidic channel with an inclined surface may enable a smooth, continuous transition between different portions of the microfluidic channel with different channel heights.
In some embodiments, an inclined surface of a microfluidic channel may be inclined in a direction that is aligned with the direction in which the microfluidic channel extends. For example, at least a portion of a microfluidic channel may extend between an inlet and an outlet of the channel. The inlet may be associated with a shorter channel height than the outlet. Accordingly, the microfluidic channel may be inclined in the direction in which the microfluidic channel extends (e.g., in a direction from the inlet to the outlet) such that a fluid in the channel flows down the inclined surface from the inlet to the outlet. A capillary pressure gradient from the inlet to the outlet may urge fluid introduced in the inlet to flow toward the outlet.
In some embodiments, an inclined surface of a microfluidic channel may be inclined in a direction that is transverse to the direction in which the microfluidic channel extends. A microfluidic channel with a transverse inclination may promote flow in a direction transverse to the length of the microfluidic channel. For example, if a microfluidic channel extends from an inlet to an outlet, a first portion of the microfluidic channel (e.g., the left side) may extend along at least a portion of a length of the channel and may be associated with a shorter channel height than a second portion of the channel disposed on and extending along at least a portion of an opposite side of the microfluidic channel (e.g., the right side). Accordingly, a capillary pressure gradient from the first portion of the microfluidic channel to the second portion of the microfluidic channel may urge fluid to flow from the first portion of the microfluidic channel to the second portion of the microfluidic channel. It should be appreciated that additional parameters (e.g., other channel dimensions, fluid surface tension) may affect the flow patterns and/or flow directions within a particular microfluidic channel. In some embodiments, the first portion of the microfluidic channel may fill before any transverse flow (e.g., from the first portion toward the second portion) occurs. In some embodiments, transverse flow may begin before the first portion fills completely. In some embodiments, the second portion of the microfluidic channel may fill before the first portion of the microfluidic channel fills as a fluid is introduced into an inlet of the microfluidic channel.
Such transverse fluid flow may be advantageous in applications that include mixing a fluid with one or more reagents (e.g., dried reagents). In a conventional microfluidic channel with a uniform channel height, a dehydrated reagent disposed within the channel may simply be flushed through the outlet of the channel before sufficient mixing has occurred, as the primary fluid flow is in a single direction from the inlet of the microfluidic channel to the outlet of the microfluidic channel. However, in a microfluidic channel with different heights and one or more inclined surfaces, a dried reagent may be disposed along a length of a microfluidic channel on the side of the channel with an increased channel height (e.g., at the bottom of an inclined surface). The associated transverse flow of fluid within the channel before the fluid exits an outlet of the channel may promote better mixing and more uniform concentrations of the reagent within the fluid along the length of the channel.
In some embodiments, a microfluidic device may include a microfluidic channel with one or more inclined surfaces extending in different directions. For example, a microchannel may include an inclined surface that is inclined at least partly in a direction in which the microfluidic channel extends and that is inclined at least partly in a direction that is transverse to the direction in which the microfluidic channel extends. It should be appreciated that a microfluidic channel may be inclined in any direction or any combination of directions, as the present disclosure is not limited in this regard.
Additionally, it should be appreciated that the disclosure is not limited to layer- or film-based manufacturing methods. For example, a microfluidic channel with an inclined surface may be manufactured using a mold formed from an additive manufacturing process or any other appropriate microfluidic device manufacturing technique as the current disclosure is not limited to how the microfluidic devices are manufactured.
As explained in greater detail, the microfluidic devices described herein may be used for a wide variety of applications, including, for example, electrochemical detection (e.g., affinity-based electrochemical detection). In some embodiments, the microfluidic device may comprise or otherwise be associated with an electrochemical detection sensor. Such devices may be configured to detect viral antibodies, such as COVID-19 antibodies, although other types of antibodies are also possible as the disclosure is not meant to be limiting in this regard.
The disclosed microfluidic devices and associated manufacturing methods offer several benefits relative to conventional microfluidic devices. For example, in some embodiments, the disclosed devices and methods may offer: significant cost reductions; reduced (or no) need for additional surface treatments; longer shelf life due to the use of more stable materials; reduced fabrication and assembly times; the ability to mass-produce microfluidic devices; reducing or eliminating the need for external peripherals and actuators such as valves and pumps; as well as other potential benefits. Combining layers with various surface properties and patterned surface treatment enables fabrication of new capillary structures with robust functionalities that work with a wide array of liquids, samples, and reagents, even those with low surface tensions. Embodiments in which a particular microfluidic device offers benefits different than those noted above are also contemplated as the disclosure is not limited to any particular application and/or design of a microfluidic device.
It should be understood that while specific microfluidic devices with various components such as the illustrated channels, valves, and reservoirs are described relative to the figures, other configurations of microfluidic devices using the methods and systems described herein are also contemplated. Accordingly, it should be understood that the microfluidic devices disclosed herein may comprise any of a variety of additional elements. In some embodiments, for example, a microfluidic pump may be provided to facilitate fluid flow through one or more channels of the microfluidic device. In other embodiments, an electrochemical detection sensor may be coupled to the microfluidic device to facilitate affinity-based electrochemical detection, as explained in greater detail below.
Turning to the figures, specific non-limiting embodiments are described in further detail. It should be understood that the various systems, components, features, and methods described relative to these embodiments may be used either individually and/or in any desired combination as the disclosure is not limited to only the specific embodiments described herein.
To maintain the various layers of a microfluidic device in a desired configuration, it may be desirable to bond, or otherwise hold, the layers in the desired configuration. For example, adhesives, heat bondable materials, compression, dry lamination techniques, and/or any other appropriate method of holding a stack of layers in a desired configuration may be used. In one such embodiment, an adhesive (e.g., a pressure sensitive adhesive, a photo-curable adhesive, or any other appropriate adhesive) may be used to bond the individual layers to one another. Referring, for example, to
As noted above, in some embodiments, an adhesive may be used to bond one or more, and in some instances, all of the layers of a microfluidic device together. In some embodiments using adhesives, the adhesive may be applied as a coating on one or both sides of an individual layer, on a surface of an adjacent layer, and/or as a separate layer disposed between two opposing layers. Additionally, in some embodiments, one or more layers, such as an intermediate layer of a device, may be formed from an adhesive material. Thus, it should be understood that the current disclosure is not limited to where or how an adhesive is applied to bond the top layer, the one or more intermediate layers, and/or the substrate to one another. Appropriate types of adhesives may include, but are not limited to, pressure sensitive adhesives (PSAs), light curable adhesives, delayed-tack adhesives, and/or any other appropriate type of adhesive as the disclosure is not so limited. For example, in certain embodiments, a layer may include a film made from a PSA (e.g., a silicone PSA), a polymer, or a copolymer film coated with a PSA (e.g., a polyester, polypropylene, or styrene-ethylene-butylene-styrene film coated with a PSA). Specific examples may include, but are not limited to, a single-sided silicone transfer adhesive with two polyester film release liners (e.g., ARclad® IS-8026); a double-sided polypropylene adhesive coated on both sides with a silicone pressure sensitive adhesive between two polyethylene terephthalate (PET) release liners (e.g., ARseal™ 90880); a single-sided hydrophobic microfluidic diagnostic tape with delayed-tack adhesive (e.g., 9795R from 3M™), and/or a single-sided hydrophilic pressure-sensitive adhesive protected by a clear siliconized polyester release liner (e.g., ARflow® 93049 (Developmental)).
In addition to the above, it is also possible that at least two of the individual layers of a microfluidic device may be bonded to each other without the use of adhesives. For example, in some embodiments, one or more layers of a microfluidic device may either be laminated to one another using a heat-based process, a chemical bonding process of the layers (e.g., dry bond lamination), and/or any other appropriate non-adhesive based bonding method, such as, for example, plasma activated bonding and/or extrusion lamination. Alternatively, the individual layers may be mechanically held in a desired configuration using clamps, fixtures, or other mechanical arrangements that apply a compressive force to the stacked layers to maintain the layers in a desired configuration during operation.
While specific embodiments using adhesives and non-adhesive bonding are described above, it should be understood that the disclosure is not limited to how the individual layers are bonded to one another. Accordingly, a stack of individual layers may either be bonded wholly with adhesives, wholly without adhesives, and/or some layers may be bonded with adhesives while other layers are bonded without adhesives.
Although
In view of the above, it should be understood that by stacking multiple intermediate layers on one another with desired patterns of removed material formed in each layer, it is possible to define multiple fluidly connected microfluidic components including microfluidic channels, valves, reservoirs, and/or any other appropriate microfluidic component that are located either in one or multiple intermediate layers of the device. Additionally, the formed components may either by hydraulic and/or pneumatic depending on the desired application and layout.
Depending on the size, shape, and/or surface properties of the patterns formed in the various layers, the substrate, intermediate layers, and/or top layer may be used to provide a number of different flow characteristics for the different components formed in a microfluidic device as disclosed herein. For example, in some embodiments, a substrate, intermediate layer, and/or top layer may be configured to facilitate fluid transport through one or more microfluidic channels of the microfluidic device. Referring to
Depending on the desired functionality, and the number of layers involved, the substrate, one or more intermediate layers, and top layer may either have the same or different hydrophobicities. For example, a substrate may have a first hydrophobicity, the one or more intermediate layers may have one or more second hydrophobicities, which may either be the same and/or different from one another, and the top layer may have a third hydrophobicity. In instances where it is desirable to retard the flow of a liquid through a particular feature, a layer with a larger hydrophobicity, i.e., more hydrophobic and less hydrophilic, may include a surface that is exposed to the interior volume of that portion of a microfluidic device. Alternatively, when it is desirable to promote the flow of a liquid through a particular feature, a layer with a smaller hydrophobicity, i.e., less hydrophobic and more hydrophilic, may include a surface that is exposed to the interior volume of the portion of the microfluidic device. Various combinations of different layers with different relative hydrophobicities are elaborated on in more detail below with regards to the disclosed embodiments.
As used herein, the term hydrophobic is given its ordinary meaning in the art and generally refers to a material that has a water contact angle greater than 90 degrees. Correspondingly, a hydrophilic material may generally refer to a material that has a water contact angle that is less than 90 degrees. In some embodiments, one or more capillary microfluidic elements require a certain range of contact angles to make them functional, as is described in further detail below.
It should be understood that the various substrates, intermediate layers, and top layer may be made from any appropriate material providing the desired functionalities for each layer. That said, in some embodiments, the substrate, one or more intermediate layers, and/or top layer of a microfluidic device may comprise: polymer films such as silicone, polyester, polypropylene, and other appropriate polymer films; copolymer films such as styrene-ethylene-butylene-styrene copolymer films, and/or polymers or other materials treated with hydrophilic or hydrophobic coatings. Additionally, the top layer and/or substrate of a microfluidic device as described herein may also be made from thicker non-film-based structures such as glass, bulk polymers, bulk copolymers, polymers or other materials treated with hydrophilic or hydrophobic coatings, photopolymers and/or resins used in three-dimensional (3D) printing, and/or any other appropriate material capable of functioning as a substrate and/or top layer for a microfluidic device as described herein. In some embodiments, it may be desirable to observe a flow of liquid through a microfluidic device. Accordingly, in some instances, the substrate, one or more intermediate layers, and/or top layer of a microfluidic device may be made from a transparent material.
As noted above, in some embodiments, a substrate, one or more intermediate layers, and/or a top layer may be made from a hydrophilic material. For example, hydrophilic polymers or other materials treated with hydrophilic coatings may be used. Additionally, the substrate and/or top layer may be made from a hydrophilic glass. Alternatively, the one or more layers of a microfluidic device may be made from a material that is modified to be hydrophilic. For instance, in some embodiments, a polymer film, or other structure depending on the particular component, may be coated with a hydrophilic material. Non-limiting examples of such materials include, but are not limited to, polymers coated with polyvinyl alcohol (PVA), a clear polyester film coated on one side with a hydrophilic coating (e.g., 3M™ 9984 Diagnostic Microfluidic Surfactant Free Fluid Transport Film); a double-sided clear polyester film coated on both sides with a hydrophilic coating (e.g., 3M™ Microfluidic Diagnostic Film 9960, 3M™ Microfluidic Diagnostic Film 9962); and/or a single-sided hydrophilic pressure-sensitive adhesive protected by a clear siliconized polyester release liner (e.g., ARflow® 93049 (Developmental)).
In addition to the above, a substrate, one or more intermediate layers, and/or a top layer may also comprise a hydrophobic material. Similar to the above, these layers may be made from a material that is inherently hydrophobic and/or a less hydrophobic material may be coated with a more hydrophobic material as the disclosure is not so limited. In certain embodiments, for example, the substrate, one or more intermediate layers, and/or top layer may be made from: a hydrophobic polymer such as polypropylene; polydimethylsiloxane (PDMS); a cyclic olefin copolymer (COC); poly(methyl methacrylate) (PMMA); photopolymers used in 3D printing; a hydrophobic copolymer such as styrene-ethylene-butylene-styrene; and/or any other appropriate hydrophobic material. Non-limiting examples of such materials include, but are not limited to, a single-sided silicone transfer adhesive with two polyester film release liners (e.g., ARclad® IS-8026); a double-sided polypropylene adhesive coated on both sides with a silicone pressure sensitive adhesive between two PET release liners (e.g., ARseal™ 90880); a styrene-ethylene-butylene-styrene film; a single-sided hydrophobic microfluidic diagnostic tape with delayed-tack adhesive (e.g., 9795R from 3M™); and/or a nitrile phenolic based thermosetting adhesive film (e.g., Thermal Bonding Film 583 from 3M™).
According to certain embodiments, the microfluidic device may comprise a plurality of intermediate layers, wherein at least one intermediate layer comprises a film and/or an adhesive (e.g., a polyester film, a pressure sensitive adhesive, etc.) and at least one intermediate layer comprises a polymer (e.g., polypropylene, PDMS, a COC, PMMA, etc.). Configuring the device in this way advantageously provides the ability to increase the thickness of the one or more intermediate layers that comprise a polymer, which may result in an increase in the overall liquid volume that the device is capable of handling (e.g., in the reservoirs and/or microfluidic channels of the one or more intermediate layers). In some embodiments, for example, the one or more intermediate layers comprising a polymer may be comparatively thick and used to define the microfluidic channels and reservoirs, while the one or more intermediate layers comprising a film and/or adhesive may be comparatively thin and used to define the functional capillary elements (e.g., valves). Suitable thicknesses of the intermediate layers are explained in further detail herein.
At least a portion of the substrate may be configured such that a side of the substrate facing the one or more intermediate layers has any of a variety of suitable (e.g., hydrophilic or hydrophobic) water contact angles. Referring to
In certain embodiments, at least a portion of one or more of the intermediate layers and/or the top layer may have any of a variety of suitable (e.g., hydrophilic) water contact angles. In some embodiments, one or more of the intermediate layers and/or the top layer has a hydrophilic water contact angle greater than or equal to 5 degrees, greater than or equal to 10 degrees, greater than or equal to 15 degrees, greater than or equal to 20 degrees, greater than or equal to 25 degrees, greater than or equal to 30 degrees, greater than or equal to 35 degrees, greater than or equal to 40 degrees, greater than or equal to 45 degrees, greater than or equal to 50 degrees, greater than or equal to 55 degrees, greater than or equal to 60 degrees, greater than or equal to 65 degrees, greater than or equal to 70 degrees, greater than or equal to 75 degrees, greater than or equal to 80 degrees, or greater than or equal to 85 degrees. In certain embodiments, one or more of the intermediate layers and/or the top layer has a hydrophilic water contact angle less than or equal to 90 degrees, less than or equal to 85 degrees, less than or equal to 80 degrees, less than or equal to 75 degrees, less than or equal to 70 degrees, less than or equal to 65 degrees, less than or equal to 60 degrees, less than or equal to 55 degrees, less than or equal to 50 degrees, less than or equal to 45 degrees, less than or equal to 40 degrees, less than or equal to 35 degrees, less than or equal to 30 degrees, less than or equal to 25 degrees, less than or equal to 20 degrees, less than or equal to 15 degrees, or less than or equal to 10 degrees. Combinations of the above recited ranges are also possible (e.g., one or more of the intermediate layers and/or the top layer has a hydrophilic water contact angle greater than or equal to 5 degrees and less than or equal to 90 degrees, one or more of the intermediate layers and/or the top layer has a hydrophilic water contact angle greater than or equal to 10 degrees and less than or equal to 30 degrees). Other ranges are also possible.
In certain embodiments, at least a portion of the one or more of the intermediate layers and/or the top layer may have any of a variety of suitable (e.g., hydrophobic) water contact angles. In some embodiments, one or more of the intermediate layers and/or the top layer has a hydrophobic water contact angle greater than or equal to greater than or equal to 90 degrees, greater than or equal to 95 degrees, greater than or equal to 100 degrees, greater than or equal to 105 degrees, greater than or equal to 110 degrees, greater than or equal to 115 degrees, greater than or equal to 120 degrees, greater than or equal to 125 degrees, greater than or equal to 130 degrees, greater than or equal to 135 degrees, greater than or equal to 140 degrees, greater than or equal to 145 degrees, greater than or equal to 150 degrees, greater than or equal to 155 degrees, greater than or equal to 160 degrees, or greater than or equal to 165 degrees. In certain embodiments, one or more of the intermediate layers and/or the top layer has a hydrophobic water contact angle less than or equal to 170 degrees, less than or equal to 165 degrees, less than or equal to 160 degrees, less than or equal to 155 degrees, less than or equal to 150 degrees, less than or equal to 145 degrees, less than or equal to 140 degrees, less than or equal to 135 degrees, less than or equal to 130 degrees, less than or equal to 125 degrees, less than or equal to 120 degrees, less than or equal to 115 degrees, less than or equal to 110 degrees, less than or equal to 105 degrees, less than or equal to 100 degrees, or less than or equal to 95 degrees. Combinations of the above recited ranges are also possible (e.g., one or more of the intermediate layers and/or the top layer has a hydrophobic water contact angle greater than or equal to 90 degrees and less than or equal to 170 degrees, the side of the substrate facing the one or more intermediate layers has a hydrophobic water contact angle greater than or equal to 100 degrees and less than or equal to 110 degrees). Other ranges are also possible.
In the depicted embodiment, and in the other various embodiments described herein, each of the substrate, one or more intermediate layers, and top layer may have any of a variety of suitable thicknesses. In certain embodiments, for example, one or more layers may be relatively thin to sufficiently control fluid pressures, and one or more layers may be relatively thick to hold more liquid volume in the device. Referring to
As described above, in some embodiments, the thickness of one or more layers (e.g., one or more intermediate layers) may be comparatively thick relative to other layers of the microfluidic device. Configuring the device in this way advantageously allows for the ability to increase the overall volume of liquid that the microfluidic device is capable of handling. In some embodiments, for example, an intermediate layer comprising a polymer may define one or more microfluidic channels and/or one or more reservoirs of the device. In some embodiments, such an intermediate layer may be comparatively thick relative to other layers of the device in order to increase the volume of reservoirs and liquids running on the microfluidic device at any given time. The relatively thick intermediate layer may have any of a variety of suitable thicknesses. Without wishing to be bound by theory, the thickness of the one or more relatively thick intermediate layers may depend on the liquid volume required for operation of the microfluidic device, as the thickness of the one or more relatively thick intermediate layers does not have a significant effect on the capillary pressure of the microfluidic device, which is instead defined by one or more relatively thin intermediate layers. In some embodiments, for example, the relatively thick intermediate layer may have a thickness between greater than or equal to 500 micrometers and less than or equal to 2 millimeters. The relatively thinner layers of the device may, in some embodiments, define one or more functional capillary elements (e.g., valves). In certain embodiments, the relatively thin intermediate layer may have a thickness between greater than or equal to 1 micrometer and less than or equal to 2 millimeters, or a thickness between greater than or equal to 1 micrometer and less than or equal to 500 micrometers.
Having described the structures associated with
In some embodiments, one or more intermediate layers are manufactured with a set of corresponding patterns where portions of material have been removed. At least portions of the patterns of the individual layers align with one another when stacked together such that the layers define a plurality of interconnected channels, reservoirs, valves, and/or other microfluidic components. The patterns of removed material in the intermediate layers may be formed, in some embodiments, by cutting, stamping, punching, and/or etching the patterns into the one or more intermediate layers. In certain non-limiting embodiments, for example, the patterns corresponding to the plurality of channels, reservoirs, valves, and/or other microfluidic components may be cut into the one or more intermediate layers using plot cutters and/or laser cutters, such as a Silhouette portrait craft cutter (Silhouette America, Lindon, UT) and/or a Graphtec Cutting Plotter CE-5000 (Graphtec America, Inc., Irvine, CA). Of course, any other appropriate method of forming a pattern in the one or more intermediate layers may also be used. In certain embodiments, for example, the patterns corresponding to the plurality of channels, reservoirs, valves, and/or other microfluidic components are formed in the one or more intermediate layers by 3D-printing. Different fabrication methods (e.g., cutting, stamping, punching, etching, 3D-printing, etc.) of the one or more intermediate layers can affect the surface properties of the layer. Accordingly, the capillary pressure can advantageously be tuned for a particular application by choosing the fabrication method.
After forming the desired patterns in the one or more intermediate layers, the method may include applying the one or more intermediate layers to a substrate. Referring, for example, to
As noted previously, the various layers of a microfluidic device may be held in a desired configuration using any number of different methods. For example, one or more adhesives may be placed between the various interfaces between the different layers. In one such embodiment, an adhesive may be disposed between the interfaces between the substrate and one or more intermediate layers, between adjacent intermediate layers, and/or between the top layer and a topmost one of the one or more intermediate layers. Depending on the type of adhesive used, different manufacturing methods may be implemented. For example, in the instance of a pressure sensitive adhesive, the act of pressing two layers together may bond the layers. Alternatively, in instances where a photo-curable adhesive is used, a light source that is at least partially transparent to the intervening layers of material may be applied to the stack of layers either after each layer is assembled and/or after all of the layers are assembled to cure the adhesive and bond the layers together. Of course, other appropriate types of adhesives may also be used.
In other embodiments, the various layers of a microfluidic device may be bonded to each other during an assembly process using other bonding methods. For example, in some embodiments, lamination (e.g., dry bond lamination), pressure, heat, and/or other methods capable of bonding the layers together may be used. Again, depending on the particular type of bonding method used, the various layers shown in
As explained above, the microfluidic device may comprise a plurality of microfluidic channels that are defined by patterns formed in the one or more intermediate layers. Referring, for example, to
In certain embodiments, at least a portion of at least one microfluidic channel has a transverse cross-section that is orthogonal to a direction of flow through the at least one microfluidic channel.
As noted previously, the various layers of the microfluidic device may have different hydrophobicities relative to one another. Specifically, substrate 102, first intermediate layer 104a, second intermediate layer 104b, third intermediate layer 104c, and/or top layer 106 may either have the same and/or different hydrophobicities. Thus, unlike typical microfluidic systems which have a constant hydrophobicity along their transverse cross-section of the various components, the channels, valves, reservoirs, and/or other microfluidic components disclosed herein may have transverse cross-sections where at least a portion of the transverse cross section taken orthogonal to a direction of flow and/or an axis extending along a length of the microfluidic component may have a first hydrophobicity and a second portion of the transverse cross-section may have a second hydrophobicity that is different than the first hydrophobicity. Referring, for example, to
Providing the different layers with different hydrophobicities may permit the construction of unique microfluidic components including, for example, stop valves to inhibit fluid flow and/or a series of trigger valves to facilitate fluid flow, depending on the configuration of the patterned features in the various layers and the corresponding hydrophobicities of the layers and/or features. One such embodiment is shown in
The stop valve described above with reference to
While a stop valve has been shown in the above embodiment, other microfluidic structures including trigger valves may also be formed depending on the particular sizes, shapes, and relative hydrophobicities of the various layers. In some embodiments, the first portion of the transverse cross-section of the microfluidic channel has a first hydrophobicity that is greater than the second hydrophobicity of the second portion of the transverse cross-section of the microfluidic channel. In some such embodiments, first portion 310a of microfluidic channel 302, at the interface of microfluidic channel 302 and valve 303, may function as a stop valve to inhibit fluid flow, and second portion 310b of microfluidic channel 302, at the interface of microfluidic channel 302 and valve 303, may function as a trigger valve to facilitate fluid flow. Additionally, while three intermediate layers have been depicted, any appropriate number of intermediate layers may be used as the disclosure is not limited in this fashion.
As noted above, in some embodiments, a transverse cross-section of a microfluidic component, such as a microfluidic channel, valve, reservoir, or other component, has at least first and second portions of the cross-section where the surfaces exposed to the interior of the microfluidic component have different hydrophobicities and/or hydrophilicities. Accordingly, it should be understood that the different hydrophobicities and/or hydrophilicities may have any appropriate relationship relative to one another depending on a desired application. Accordingly, a first hydrophobicity (or hydrophilicity) and a second hydrophobicity (or hydrophilicity) of different layers forming the transverse cross-section of a microfluidic component may exhibit any appropriate difference for a desired application. For example, in certain embodiments, a difference between the first and second hydrophobicities or hydrophilicities may be greater than or equal to 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and/or any other appropriate percentage of the larger hydrophobicity or hydrophilicity. Correspondingly, the difference between the first and second hydrophobicities or hydrophilicities may be less than or equal to 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or any other appropriate percentage of the larger hydrophobicity or hydrophilicity. Combinations of the above recited ranges are contemplated including, for example, a difference between the first and second hydrophobicities or hydrophilicities that is between or equal to 5% and 95% of the larger hydrophobicity or hydrophilicity. However, other combinations of the foregoing ranges as well as differences between the first and second hydrophobicities or hydrophilicities both greater than and less than those noted above are also contemplated as the disclosure is not so limited.
As would be understood by a person of ordinary skill in the art, the first and second portions of the transverse cross-section of the microfluidic component having different hydrophobicities or hydrophilicities may also have different water contact angles. In some embodiments, for example, the first portion of the microfluidic component may have a first water contact angle and the second portion of the microfluidic component may have a second water contact angle, wherein a difference between the first and the second water contact angle is greater than or equal to 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or wherein a difference between the first and second water contact angle is less than or equal to 95%, 90%, 8%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. The water contact angle of the first portion and/or the second portion may, in some embodiments, be greater than or equal to 10 degrees and less than or equal to 180 degrees.
In certain embodiments, the first and second hydrophobicities or hydrophilicities of the first portion and the second portion of the microfluidic component may be the same or substantially the same, as the disclosure is not meant to be limiting in this regard.
According to some embodiments, a stop valve may be defined by more than one layer of the microfluidic system (e.g., a substrate and/or one or more intermediate layers, one or more intermediate layers) such that the surface and side walls of the microfluidic channel vary in hydrophobicities or hydrophilicities due to the surface being defined by a first layer (e.g., with a first hydrophobicity or hydrophilicity) and the side walls being defined by one or more second layers (e.g., with at least a second hydrophobicity or hydrophilicity that is different from the first hydrophobicity or hydrophilicity). In certain embodiments, for example, a bottom surface of a microfluidic channel defined by, for example, the first hydrophilic layer may be hydrophilic (or less hydrophobic), and the side walls of the microfluidic channel defined by, for example, the one or more second layers may be more hydrophobic (or less hydrophilic) than the surface of the first layer exposed to an interior of the channel. In some embodiments, while the hydrophilic (or less hydrophobic) bottom surface may be configured to facilitate fluid flow, the hydrophobic (or less hydrophilic) side walls advantageously stop liquid flow, therefore functioning as a stop valve.
In certain embodiments, for example, a bottom surface of at least a portion of at least one microfluidic channel may have a first hydrophilicity or hydrophobicity. In some embodiments, the bottom surface of at least portion of at least one microfluidic channel may be hydrophilic. The bottom surface of the portion of the at least one microfluidic channel may, in some embodiments, be defined by an intermediate layer. Referring to
According to some embodiments, a bottom surface of at least a portion of at least one microfluidic channel may be defined by a substrate. Referring, for example, to
According to certain embodiments, a single intermediate layer of the device may be configured to function as a stop valve by modifying the surface properties of a portion of the intermediate layer. In some embodiments, for example, a portion of the intermediate layer may be patterned to change the degree of hydrophilicity or hydrophobicity of the portion relative to the remainder of the microfluidic channel such that the portion can function as a stop valve.
In certain embodiments, a bottom surface of at least a portion of at least one microfluidic channel may have a first hydrophobicity. In some embodiments, the bottom surface of at least a portion (e.g., the middle portion) of the at least one microfluidic channel may be hydrophobic. For example, the bottom surface of the portion of the at least one microfluidic channel may, in some embodiments, be defined by a substrate. According to some embodiments, one or more side walls of the intermediate layer may have a second hydrophobicity that is more hydrophobic than the bottom surface of the portion of the at least one microfluidic channel. For example, the second hydrophobicity may be at least 5% greater, 10% greater, 15% greater, 20% greater, 35% greater, 40% greater, 45% greater, or more than the first hydrophobicity. In some embodiments, the one or more side walls of the portion of the at least one microfluidic channel may, in certain embodiments, be defined by one or more intermediate layers.
In some embodiments, the sides and/or other surfaces of the layers and/or channels can be modified to be either more or less hydrophobic using any appropriate method including inherent material properties, surface treatments, laser etching, and/or any other appropriate type of treatment to provide a desired surface property for one or more portions of the microfluidic devices described herein.
As described herein, a microfluidic device may, in some embodiments, comprise a microfluidic channel having a gap or area of increased hydrophobicity in between two separated portions of the channel. For example, in certain embodiments, a channel has a middle portion disposed between two opposing portions of the channel extending along a length of the channel, wherein the middle portion isolates liquids separately contained in one or both of the opposing portions of the channel. Such a configuration may, in some embodiments, be fabricated using individual layers of films to form different portions of the microfluidic channel, as described in further detail below.
As shown in
Surfaces in channel 302d may exhibit different hydrophobicities such that one or more fluids may be isolated in the first and second portions 350a and 350b of the channel without entering the recessed portion of the channel (i.e., third portion 350c) and/or without intermixing with each other, based on capillary pressure. This can be accomplished by having at least one surface of the third portion of the channel be more hydrophobic than adjacent surfaces of the first portion of the channel and the second portion of the channel. For example, at least side wall 408a may be more hydrophobic than surface 414a. Alternatively, or additionally, at least side wall 408b may be more hydrophobic than surface 414b. However, to permit the two volumes to be intermixed, it may also be desirable to facilitate the flowing of a liquid through the recessed portion of the channel. Thus, in some embodiments, bottom surface 112 of the recessed portion of the channel may be less hydrophobic (i.e., more hydrophilic) than the surfaces of side walls 408a and 408b of the recessed portion of the channel. This may permit a liquid to be selectively flowed through the recessed portion of the channel to permit intermixing of liquids contained in the isolated portions of the primary channel as elaborated on below. Accordingly, one or more liquids may be confined within the first and second portions 350a and 350b without entering the recessed portion, i.e., third portion 350c, of channel 302d. In effect, a stop valve is created to pin fluids in the first and second portions of channel 302d based on the capillary pressure due to the difference in hydrophobicity between surfaces in the recessed portion of the channel and adjacent surfaces in the primary channel prior to use.
It should be appreciated that while exemplary constructions of capillary stop valves fabricated using layers of films are discussed above in reference to
While liquids are illustrated in the two isolated portions of the primary channel, dried solids, such as one or more dried reagents, may also be disposed in one of the isolated portions of the primary channel and a liquid may be disposed in the other isolated portion of the primary channel such that upon intermixing of the volumes, the one or more dried reagents may be reconstituted in an even fashion along a length of the channel. For example, in some embodiments, one or more surfaces such as top surfaces 414a and 414b in the primary channel as shown in
Some aspects of the present disclosure are directed to a method of operating a microfluidic device to perform functions such as reconstitution of dried reagents, dilution and mixing of reagents, and others. In some embodiments, a microfluidic device similar to those shown in
In some embodiments, an intermediate layer is configured to at least partially define a first microfluidic channel and a second microfluidic channel that intersect with each other. Sec, for example,
According to some embodiments, an interface between the first microfluidic channel and the second microfluidic channel, which in the depicted embodiment corresponds to a portion of the second microfluidic channel adjacent to the intersection of the first channel and the second channel, may be patterned such that the interface is configured to function as a stop valve. Referring again to
According to some embodiments, the water contact angle at the interface may, in some embodiments, be higher than the water contact angle of the first microfluidic channel (e.g., channel 302) and/or the second microfluidic channel (e.g., primary channel 312) to be able to stop a liquid flow and function as a stop valve (e.g., stop valve 303). In certain embodiments, the value of the water contact angle can vary with different liquids and the hydrophobicity of the interface may be adjusted accordingly.
The interface between the first microfluidic channel and the second microfluidic channel may be patterned using any of a variety of suitable means to increase a hydrophobicity and/or water contact angle of the surface corresponding to the interface relative to adjacent portions of the second microfluidic channel. In certain embodiments, for example, the interface between the first microfluidic channel and the second microfluidic channel is laser etched and/or engraved. In some embodiments, cutting one or more thin cuts through the interface may form a hydrophobic barrier that can stop liquid advancement, therefore allowing the interface to function as a stop valve.
In some embodiments, the surface of the microfluidic channel (e.g., channel 302) may have a first hydrophobicity or hydrophilicity, and patterning the interface by laser etching and/or engraving causes the interface to have a second hydrophobicity or hydrophilicity that is different from the first hydrophobicity or hydrophilicity of the surface of the remainder of the channel. Referring, for example, to
The interface between the first microfluidic channel and the second microfluidic channel may have any of a variety of suitable patterned designs. In some embodiments, for example, and as shown in
In certain embodiments, the stop valve formed at the interface of the first microfluidic channel and the second microfluidic channel may be used to merge the first fluid stopped at the stop valve with a second fluid. Referring, for example, to
The capillary pressure of the microfluidic channels may be controlled in ways other than just tuning the hydrophobicity and/or hydrophilicity of portions of the microfluidic channels. In some embodiments, for example, changing the geometry and/or dimensions of a microfluidic channel may also cause the channel to act as a valve (e.g., a retention valve, a stop valve). As explained herein, a plurality of intermediate layers may be configured to at least partially define a plurality of fluidly connected microfluidic components (e.g., channels, reservoirs, and/or valves). In certain embodiments, a portion of at least one microfluidic channel is fluidly connected to and proximate a reservoir. See, for example,
According to some embodiments, second intermediate layer 104b may be disposed on top of first intermediate layer 104a. Second intermediate layer 104b may be a hydrophobic layer such that second intermediate layer 104b is more hydrophobic than first intermediate layer 104a, in certain embodiments. For example, second intermediate layer 104b may have a hydrophobicity that is at least 5% greater, 10% greater, 15% greater, 20% greater, 35% greater, 40% greater, 45% greater, or more than first intermediate layer 104a.
In certain embodiments, first intermediate layer 104 and second intermediate layer 104b may have the same hydrophobicity or hydrophilicity, however the water contact angle of one or more portions and/or components of first intermediate layer 104a and/or second intermediate layer 104b may be adjusted to stop and/or facilitate the flow of liquid through the one or more portions and/or components of first intermediate layer 104a and/or second intermediate layer 104b.
In some embodiments, a portion of second intermediate layer 104b (e.g., hydrophobic layer) exposed to an interior of a portion of microfluidic channel 302 has a first transverse dimension at an upstream location and a second transverse dimension at a downstream location, wherein the first transverse dimension is smaller than the second transverse dimension. Referring, for example, to
Advantageously, such a gradual change from a smaller, first transverse dimension to a larger, second transverse dimension may, in some embodiments, result in the portion of the at least one microfluidic channel functioning as a retention valve. In certain embodiments wherein the second intermediate layer is a hydrophobic layer that is more hydrophobic than the first intermediate layer, for example, the transition from the first transverse dimension to the second transverse dimension results in a liquid in the microfluidic channel being exposed to a larger surface area of hydrophobic material at an upstream location (e.g., at the inlet) of the microfluidic channel that transitions to a smaller surface of hydrophobic material area at a downstream location of the microfluidic channel. The pressure gradient (e.g., capillary pressure gradient) at the first transverse dimension may be greater than the pressure gradient at the second transverse dimension, resulting in portion 706 of microfluidic channel 302a functioning as a retention valve for a liquid in microfluidic channel 302a. In some non-limiting embodiments, a triangular geometry, as shown in
Any of a variety of suitable dimensions may be employed for the first transverse dimension and the second transverse dimension as long as the portion of the hydrophobic layer exposed to the interior of the microfluidic channel is configured such that a first, comparatively smaller transverse dimension transitions into a second, comparatively larger transverse dimension.
As explained herein, the fluidly connected microfluidic components may be defined by more than two intermediate layers (e.g., three intermediate layers). Although
As described herein, a microfluidic device may, in some embodiments, comprise a microfluidic channel having a transverse cross-section that is orthogonal to a direction of flow through the microfluidic channel, wherein a first portion of the transverse cross-section has a first channel height, and a second portion of the transverse cross-section has a second channel height that is different from the first channel height. Such a configuration may, in some embodiments, be fabricated using individual layers of films to form different portions of the microfluidic channel, as described in further detail below.
Third layer 530 is disposed on first layer 510 at first location 113, and third layer 530 is disposed on second layer 520 at second location 123 which may be located upstream from the first location along a length of the channel. Third layer 530 is inclined in region 133 between first location 113 and second location 123. A region of a layer of a microfluidic device may be inclined relative to another portion of the microfluidic device. For example, referring to
In the embodiment of
In the embodiment of
Microfluidic device 100h may include reagent 250 disposed in microfluidic channel 302f. Specifically, in the depicted embodiment, reagent 250 may be disposed in second region 242. In some embodiments, reagent 250 may be disposed along at least a portion of a length of the second portion 242 of microfluidic channel 302f in the direction in which the microfluidic channel 302f extends (i.e., in the first direction aligned with the Y direction). The reagent may be disposed continuously along the microfluidic channel or in discrete groupings, as the disclosure is not so limited. For example,
Without wishing to be bound by theory, a microfluidic channel with different heights in different portions of the microfluidic channel may be associated with a capillary pressure gradient. As described above, the height of first portion 241 of microfluidic channel 302f is less than the height of second portion 242. As such, microfluidic channel 302f may be associated with a capillary pressure gradient in which the capillary pressure associated with first portion 241 may be greater than the capillary pressure associated with second portion 242. Accordingly, a fluid disposed within microfluidic channel 302f may be urged to flow from first portion 241 to second portion 242. That is, a fluid disposed within the microfluidic channel 302f may be urged to flow down the inclined region 133.
When fluid is introduced into inlet 252 of microfluidic channel 302g, the fluid may flow at least partially in the second direction before reaching outlet 254. Depending on certain parameters of the microfluidic channel and of the fluid, different flow patterns may be prescribed. As described above in reference to
In some embodiments, a method may include introducing a fluid into a first portion of a microfluidic channel extending in a first direction. The first portion of the microfluidic channel may include an inlet of the microfluidic channel in some embodiments. The method may include flowing the fluid in a second direction transverse to the first direction from the first portion of the microfluidic channel to a second portion of the microfluidic channel. The first portion of the microfluidic channel and the second portion of the microfluidic channel may be at least partially coextensive along a length of the microfluidic channel. The method may include flowing the fluid out of the second portion of the microfluidic channel to an outlet of the microfluidic channel. The outlet of the microfluidic channel may be spaced from the first portion of the microfluidic channel in the first direction.
Third layer 530 is inclined in region 133 between first location 113 and second location 123. Microfluidic device 100j of
Third layer 530 is inclined in region 133 between first location 113 and second location 123. Microfluidic device 100k of
It should be appreciated that different combinations and/or arrangements of layers may be appropriate in different embodiments of a microfluidic device. In some embodiments, each layer may be associated with a separate film of material. In some embodiments, a single film of material may be associated with multiple layers. For example, a planar film of material may be partially cut to form a flap that is subsequently tucked underneath or disposed on top of another portion of the same film of material, thereby forming an inclined surface. In this way, a single planar film of material may be modified to form multiple separate layers of a microfluidic device.
In some embodiments, stop valves 303 are disposed between each adjacent liquid channel and pneumatic channel and may correspond to channels formed in the intermediate layers (e.g., the second and third intermediate layers). Accordingly, liquid present in one liquid channel is pinned at the interface with the stop valves formed in the intermediate layers due to the unpatterned hydrophobic surface of the first intermediate layer being exposed to the channel forming the stop valve or due to hydrophobic side walls formed by cutting through one or more hydrophilic surfaces of the layer, and thus, preventing liquid from entering the pneumatic channel.
Plurality of trigger valves 308 in fluid communication with each liquid channel may provide fluid communication between the associated liquid channel and primary channel 312. In the depicted embodiment, the trigger valves are formed in the third intermediate layer. Thus, the hydrophilic surface of the second intermediate layer exposed to the interior of the trigger valves may draw liquid to the interface between the trigger valves and the primary channel. Accordingly, liquid flowing through the primary channel may trigger flow from the reservoirs to the primary channel through the trigger valves as each trigger valve is triggered in sequence due to the flow of liquid passing through the primary channel. The combined flow of liquids may then flow into outlet 314 formed in each of the intermediate layers. The liquid flow can be triggered and/or stopped by forming hydrophobic barrier 315 at the end of one or more channel. In some embodiments, hydrophobic barrier 315 may be engraved and/or cut to stop liquid flow at the end of the one or more channels and trigger liquid flow from the one or more channels by flowing a liquid in the primary channel.
The microfluidic device may be used for any of a variety of suitable applications. In some embodiments, for example, the microfluidic device is used to perform affinity-based electrochemical detection. Accordingly, in some embodiments, the microfluidic device may comprise or otherwise be associated with an electrochemical detection sensor. The electrochemical detection may be performed, in some embodiments, by delivering different liquid samples and reagents sequentially from the reservoirs defined by the one or more intermediate layers. In certain embodiments, an electrochemical detection sensor (e.g., with conjugated antibodies) is placed proximate to an outlet channel or reaction chamber. Liquid samples and/or reagent may be added to an inlet of each reservoir, in some embodiments. The reservoirs may contain any of a variety of suitable samples and/or reagents. Examples include, but are not limited to, a blood sample, a plasma sample, a detection antibody, a wash buffer (e.g., phosphate-buffered saline with Tween® (PBST)), horseradish peroxidase (HRP)-conjugated streptavidin, and/or tetramethylbenzidine (TMB). In certain embodiments, stop valves at the end of the reservoirs will stop the flow to aliquot the liquid volume needed for electrochemical detection. Liquid flow from the reservoirs is triggered, in some embodiments, by adding a fluid (e.g., buffer) through the main channel of the microfluidic device (see, for example, primary channel 312 in
The following example describes the fabrication and operation of a microfluidic device.
A capillary microfluidic device was fabricated from layers of single- and double-sided adhesive tapes and thin films without any adhesive sides, similar to the system shown in
The second layer was designed to define the channels and the stop valves. The second layer was made from a 100 μm thick hydrophobic adhesive tape (e.g., 3M™ Microfluidic Diagnostic Tape 9795R or Single Sided Clear Delayed Tack Adhesive Tape). The stop valve functional section was located on the non-adhesive side of this tape.
The third layer was designed to allow liquid to flow above the stop valves. The side walls of the hydraulic channels were formed from the third layer. The third layer was mainly used to define the thickness of the channels and the volumes stored inside. The third layer was made from a 100 μm thick hydrophobic adhesive tape (e.g., 3M™ Microfluidic Diagnostic Tape 9795R). Thicker films could also be used if desired to increase the volume of features formed in this layer. The top side of the third layer was hydrophobic to avoid any liquid flow through the pneumatic air channels on the layer above it.
The fourth layer was used to define the pneumatic channels. The fourth layer was made from a 100 μm thick hydrophobic adhesive tape (e.g. 3M™ Microfluidic Diagnostic Tape 9795R). The fourth layer formed the side walls of the pneumatic air channels. The bottom part of the fourth layer was used to cover parts of the hydraulic channels. The bottom side of the fourth layer was hydrophobic to stop the liquid at the stop valves. The water contact angle of the adhesive bottom side of the fourth layer was 91 degrees.
The last layer was a hydrophobic layer used to cover the channels and the pneumatic layer. The last layer was made from a 100 μm thick hydrophobic adhesive tape (e.g., 3M™ Microfluidic Diagnostic Tape 9795R). The bottom part of the last layer was hydrophobic to avoid any liquid flow through the pneumatic air channels in the layer below it. All the layers were assembled by applying pressure manually on the adhesive tapes which included pressure sensitive adhesives.
The assembled microfluidic device is capable of being operated to perform affinity-based electrochemical detection on the device. Specifically, the manufactured device was capable of delivering different liquid samples and reagents sequentially to a biosensor as follows. First, an electrochemical detection sensor with conjugated antibodies on the surface was placed in fluid communication with an outlet channel of the device. Liquid samples and reagents were added at the inlets of each reservoir. The stop valves at the end of these reservoirs were configured to stop the flow to aliquot the liquid volume used for the next operations. The flow was triggered from these reservoirs by adding buffer through the inlet and primary channel located at the bottom of the device. Liquids were stored in the reservoirs according to the following sequence:
The device started running by draining the first and the second reservoirs simultaneously to mix the blood sample with the detection antibody. The mixture then flowed on the surface of the sensor. After draining the detection antibody in the second reservoir, the air valve opened and allowed the wash buffer in the third reservoir to drain and flow over the sensor. After the wash buffer was drained, the flow of the HRP-conjugated streptavidin was initiated by opening the air valve. The next air valve opened and another washing step was performed followed by delivering TMB on the sensor. After draining the TMB, the air valve for the last reservoir opened and allowed for the last washing step for the sensor.
The following example describes the operation of a microfluidic device for the electrochemical detection of COVID-19 antibodies.
A microfluidic device was fabricated according to Example 1. Electrochemical detection sensor 900 was placed in fluid communication with an outlet channel of microfluidic device 100f, as shown in
The device started running by delivering the sample and the reagents sequentially to the electrochemical sensor, followed by a final washing step with PBS buffer.
The working electrodes in the electrochemical sensor were spotted with NC protein that was used to capture the antibody in the plasma sample. The control electrodes were blocked with bovine serum albumin (BSA). The positive plasma sample had COVID-19 antibodies that bind to the NC protein spotted on the surface of the electrode. The enzymatic amplification steps were performed by flowing the detection antibody with HRP then TMB.
The following example describes a microfluidic device comprising a microfluidic channel having a gap or area of increased hydrophobicity in between two separated portions of the channel to separately pin one or more liquids in desired portions of the channel.
The plurality of stacked double-sided tapes may be used to fabricate one or more passive components (e.g., microfluidic channels) of a microfluidic device.
Referring to
Subsequently, a liquid (not shown) may be provided in middle portion 502c. The liquid may be provided by, for example microfluidic pump 570c, although other ways of providing a liquid into the various portions of the channel may be used including, for example, capillary pressure induced flow as the disclosure is not limited to how the liquids or other substances are introduced to the various portions of the channel. In either case, upon flowing the liquid through middle portion 502c, the liquid in the middle channel may merge with one or both of the first and second substances on both sides of the middle channel. This may then permit intermixing of the substances disposed in the first and second portions of the primary channel.
In some embodiments, the first substance and the second substance are both liquids. When a third liquid is added in the middle portion 502c, it flows in the defined path that was acting as a stop valve for the two liquids lying on the sides in the first and second portions 502a and 502b. The volume of liquids on the sides can be varied in different ratios to enable having a desired dilution ratio. In some embodiments, the entire channel 302 can act as a reservoir and be drained as a complete one liquid block once all the liquids become merged and connected inside the reservoir.
While several embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present disclosure. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present disclosure is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present disclosure.
All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.
The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”
The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of.” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.
In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
This application claims priority under 35 U.S.C. § 119 (e) to U.S. Provisional Patent Application No. 63/302,832, filed Jan. 25, 2022, U.S. Provisional Patent Application No. 63/302,863, filed Jan. 25, 2022, and U.S. Provisional Patent Application No. 63/302,865, filed Jan. 25, 2022, each of which are incorporated herein by reference in their entirety for all purposes.
Filing Document | Filing Date | Country | Kind |
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PCT/US2023/011472 | 1/24/2023 | WO |
Number | Date | Country | |
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63302832 | Jan 2022 | US | |
63302863 | Jan 2022 | US | |
63302865 | Jan 2022 | US |