The invention relates to microfluidics technology, and more particularly to a microfluidic pump for control of fluid flow through microchannels.
Microfluidics systems are of significant value for acquiring and analyzing chemical and biological information using very small volumes of liquid. Use of microfluidic systems can increase the response time of reactions, minimize sample volume, and lower reagent and consumables consumption. When volatile or hazardous materials are used or generated, performing reactions in microfluidic volumes also enhances safety and reduces disposal quantities.
Microfluidic devices have becoming increasingly important in a wide variety of fields from medical diagnostics and analytical chemistry to genomic and proteomic analysis. They may also be useful in therapeutic contexts, such as low flow rate drug delivery.
The microcomponents required for these ends are often complex and costly to produce. For example, a micropump may be used to mix reagents and transport fluids between a disposable analysis platform component of the system and an analysis instrument (e.g., an analyte reader with display functions). Yet controlling the direction and rate of fluid flow within the confines of a microfluidic device, or achieving complex fluid flow patterns inside microfluidic channels is difficult.
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A microfluidic pump has been developed in order to provide low cost, high accuracy means for onboard sample handling in disposable assay devices. Devices utilizing the microfluidic pump, as well as methods for manufacture and performing a microfluidic process are also provided.
In a first aspect, the invention provides a microfluidic pump, comprising: a microchannel defined by (a) a groove in a first surface of a first substrate, and (b) a second surface of a second substrate; and an actuator configured to compress a portion of the second substrate into the groove of the first substrate without substantially deforming the groove, characterized in that the actuator is configured to translate along an axis of the groove.
In an embodiment, the groove has a height and the height is at least about 10 microns, at least about 20 microns, at least about 30 microns, or at least about 50 microns and/or wherein the groove has a height and the height is about 1000 microns or less, about 500 microns or less, about 250 microns or less, about 125 microns or less, about 100 microns or less, about 75 microns or less.
In an embodiment, the first and second substrates are substantially planar.
In an embodiment, the channel has an inlet and an outlet and a distance between the inlet and the outlet is at least about 1 mm, at least about 2.5 mm, at least about 5 mm, at least about 10 mm, at least about 25 mm and/or wherein the channel has an inlet and an outlet and a distance between the inlet and the outlet is about 250 mm or less, 100 mm or less, about 75 mm or less, about 50 mm or less, about 25 mm or less.
In an embodiment, the pump is disposed in fluidic communication with a microfluidic device. In an embodiment, the pump comprises at least one microchannel configured to receive a liquid sample suspected of containing at least one target and the microchannel comprises at least one reagent for use in determining the presence of the at least one target. In an embodiment, the pump is configured to produce a gas pressure acting upon a distal gas-liquid interface of the liquid sample when the distal gas-liquid interface of the liquid sample is disposed within the microchannel of the microfluidic device. A proximal gas-liquid interface of the liquid sample may be exposed to an ambient atmosphere. The gas pressure acting upon the distal gas-liquid interface of the liquid sample may be less than an ambient gas pressure. The first and second substrates may be disposed within the microfluidic device. In an embodiment, the microchannel of the microfluidic device comprises the liquid sample disposed therein, optionally wherein the liquid sample comprises urine or at least one liquid component of blood. In an embodiment, the actuator is configured to provide a rate of flow of the liquid sample within the microchannel of the microfluidic device of at least about 1 nl/s, at least about 5 nl/s, at least about 10 nl/s, at least about 25 nl/s, at least about 50 nl/s, at least about 100 nl/s, at least about 250 nl/s, at least about 500 nl/s at least about 1000 nl/s and/or wherein the actuator is configured to provide a rate of flow of the liquid sample within the microchannel of the microfluidic device of about 10,000 nl/s or less, about 5,000 nl/s or less, about 2,500 nl/s or less, at least about 1000 nl/s or less. In an embodiment, a total volume of liquid sample within the microchannel is about 100 microliters or less, about 50 microliters or less, about 25 microliters or less, about 20 microliters or less.
In an embodiment, the channel has an uncompressed area and, when compressed by the actuator, the compressed portion of the second substrate occludes at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 97.5%, at least about 99%, or essentially all of the uncompressed area of the channel.
In an embodiment, in the uncompressed state, the groove has a width and the width is at least about 50 microns, at least about 100 microns, at least about 200 microns, at least about 500 microns, optionally wherein, in the compressed state, the width of the groove is at least about 75%, at least about 90%, at least about 95%, at least about 97.5%, at least about 99%, or essentially the same as in the uncompressed state.
In an embodiment, in the compressed state, the groove has a width and the width is about 2000 microns or less, about 1500 microns or less, about 1000 microns or less, about 750 microns or less about 600 microns or less, optionally wherein, in the compressed state, the height of the groove is at least about 75%, at least about 90%, at least about 95%, at least about 97.5%, at least about 99%, or essentially the same as in the uncompressed state.
In an embodiment, in the uncompressed state, the second substrate has a first thickness overlying the groove and a second thickness spaced apart laterally a first distance from the groove and wherein the second thickness is at least about 110%, at least about 125%, at least about 150%, at least about 175%, or at least about 200% greater than the first thickness, optionally wherein the first distance is at about 50% greater than a width of the groove, about 75% greater than a width of the groove, about 100% greater than a width of the groove, about 200% greater than a width of the groove.
Also disclosed is a microfluidic pump module. The microfluidic pump module may include a first plate element and a second plate element, the first plate element being elastomeric and the second plate element being non-elastomeric. The second plate element includes a microchannel formed on a surface of the second plate element, and the first and second plate elements are coupled to form a fluid tight seal along the boundary of the microchannel defining a fluid flow path.
Also disclosed is a microfluidic device utilizing the microfluidic pump module described herein. The microfluidic device includes (a) a rigid substrate having a microchannel formed on a surface thereof; and (b) a flexible layer coupled to and overlying the rigid substrate thereby enclosing the microchannel, wherein the flexible layer comprises a raised element disposed over a portion or all of the microchannel. The device further includes a fluid tight seal formed between the rigid substrate and the flexible layers along a periphery of the microchannel forming an enclosed capillary.
Also disclosed is a microfluidic device utilizing the microfluidic pump module described herein. The microfluidic device includes (a) a rigid substrate having a microchannel formed on a surface thereof; and (b) a flexible layer coupled to and overlying the rigid substrate thereby enclosing the microchannel, wherein the flexible layer has a flat surface disposed over a portion or all of the microchannel. The device further includes a fluid tight seal formed between the rigid substrate and the flexible layers along a periphery of the microchannel forming an enclosed capillary.
Also disclosed is a microfluidic device utilizing the microfluidic pump module described herein, wherein the pump module comprises at least two independent microchannels arranged in a substantially parallel manner. One or more actuators are provided which act upon the two or more microchannels simultaneously, thereby providing means to pump two fluids separate from one another. The microchannels may have identical cross sectional areas, such that the volume of fluid transported per unit distance of the microchannel is substantially the same. The at least two microchannels may have different cross sectional areas, in which instance the volume of fluid transported per unit distance of the microchannel is different.
Also disclosed is a microfluidic device utilizing the microfluidic pump module described herein, wherein the pump module comprises at least two independent microchannels arranged concentrically about a point upon which at least one actuator rotates. Where the at least two microchannels have identical cross sectional area, per revolution of the at least one actuator, a greater volume of fluid will be transported in the outermost channel according to the equation Q = rωA, where Q is the volume flow rate, r is the radius of the microchannel, ω is the angular velocity and A is the cross sectional area of the microchannel. Thus if the outermost channel has a radius r2, which is three times the radius of the inner most channel r1, then three times the volume of fluid will be transported in the outermost channel compared with the innermost channel per revolution of the actuator. The skilled person will thus readily recognize that by altering the relative ratio of cross sectional area of the respective concentric microchannels, different volumes of fluid may be transported per revolution in each respective channel.
Also disclosed is a method for performing a microfluidic process. The method includes (a) applying a voltage to a microfluidic pump module as described herein. The applied voltage activates a motor which advances an actuator element, such as one or more rollers, which is rotatably engaged with the second substrate, causing deformation of the second substrate into the microchannel formed on the surface of the first substrate. Deformation of the elastomeric second substrate into the microchannel forces fluid within the microchannel along the microchannel resulting in a fluid flow. The first substrate is formed from a material having a Shore D hardness of between about 75 and about 90. Such materials include, but are not limited to, polystyrene, polypropylene, polymethylmethacrylate, polycarbonate and the like. The microchannel or groove formed in the surface of the first substrate is dimensionally stable, by which is meant that when the second substrate is deformed into the groove in the first substrate, the width of the groove is at least about 75%, at least about 90%, at least about 95%, at least about 97.5%, at least about 99%, or essentially the same as in the uncompressed state and height the groove is at least about 75%, at least about 90%, at least about 95%, at least about 97.5%, at least about 99%, or essentially the same as in the uncompressed state. The dimensions of the groove are thus considered to be essentially unchanged as a consequence of the deformation of the second substrate into the first substrate, The second substrate is formed from a material having a Shore A hardness of between about 15 and 90. Such materials include, but are not thermoplastic elastomer (TPE), polydimethylsiloxane (PDMS), silicone rubber, fluoroelastomer and the like. Such materials are considered to be dimensionally unstable, by which is meant that when a compressive force or a stretching force is applied to such polymeric materials the material deforms, either through elongation in one or more directions, or the material compresses in one or more dimensions.
Also disclosed is a method of manufacturing a microfluidic device. The method includes coupling a rigid substrate having a microchannel formed on a surface thereof, to a flexible layer overlying the rigid substrate and enclosing the microchannel. A fluid tight seal is formed between the rigid substrate and the flexible layers along a periphery of the microchannel forming an enclosed capillary. The rigid substrate and the flexible layer are coupled via a laser welding process. The process includes:
Also disclosed is a method of manufacturing a microfluidic device. The method includes coupling a rigid substrate having a microchannel formed on a surface thereof, to a flexible layer overlying the rigid substrate and enclosing the microchannel. A fluid tight seal is formed between the rigid substrate and the flexible layers along a periphery of the microchannel forming an enclosed capillary. The rigid substrate and the flexible layer are coupled via a process of over-molding. The process includes:
A microfluidic pump and device containing the pump have been developed in order to provide, in embodiments, low cost, high accuracy and low flow rate means for onboard sample handling for disposable assay devices. Advantageously, the rate of fluid flow within the pump is essentially constant even at very low flow rates.
The pump comprises a first substrate and a second substrate secured with respect to one another to provide a structure having one or more microchannels which are sealed along the boundaries of the microchannels thereby defining fluid flow paths.
With reference to
In the compressed state, the second substrate typically occludes a sufficient portion of the microchannel (40) to displace a substantial portion of fluid from microchannel (40) at the site of compression. For example, the second substrate may occlude a sufficient portion of the microchannel (40) to separate fluid disposed within microchannel (40) on one side of the site of compression from fluid disposed within microchannel (40) on the other side of the site of compression. In embodiments, the second substrate occludes, in the compressed state, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 97.5%, at least about 99%, or essentially all of the uncompressed cross-sectional area of the groove at the site of compression.
The compression may create a fluid-tight seal between the first and second substrates within the groove at the site of compression. When a fluid-tight seal is formed, fluid, e.g., a liquid, is prevented from passing along the groove from one side of the site of compression to the other side of the site of compression.
The fluid-tight seal may be transient, e.g., the second substrate may fully or partially relax upon removal of the compression thereby fully or partially reopening the groove.
The groove has a first cross-sectional area in an uncompressed state and a second cross-sectional area in the compressed state. In embodiments, the portion of the elastomer is compressed into the groove without substantially deforming the groove. For example, a ratio of the cross-sectional area at the site of compression in the compressed state to the cross-sectional area at the same site in the uncompressed state may be at least about 0.75, at least about 0.85, at least about 0.925, at least about 0.975, or about 1. In embodiments, the height of the groove, e.g., the maximum height of the groove at the site of compression, in the compressed state may be at least about 75%, at least about 85%, at least about 90%, at least about 95%, or about 100% of the height of the groove at the same site in the uncompressed state. In embodiments, the width of the groove, e.g., the maximum width of the groove at the site of compression, in the compressed state may be at least about 75%, at least about 85%, at least about 90%, at least about 95%, or about 100% of the width of the groove at the same site in the uncompressed state.
Translation of the site of compression along the length of the microchannel (40) creates an effective pumping action resulting in flow of fluid within the microchannel (40) in the direction of the advancing deformation element (50). In some embodiments a raised element (30), such as a bump, is present on the elastomer (10), which may be placed over the microchannel region (40), thereby increasing the thickness of elastomeric material which may aid sealing of the elastomer into the channel when compressed against the non-elastic component (20). For example, in the uncompressed state, the elastomer may have a first thickness overlying the groove and a second thickness spaced apart laterally a first distance from the center of the groove. In embodiments, the second thickness is at least about 110%, at least about 125%, at least about 150%, at least about 175%, or at least about 200% greater than the first thickness. The second thickness may be at least about 500% or less, about 400% or less, about 300% or less, or at about 250% or less greater than the first thickness.
The first distance may be at least about 1 mm, at least about 2.5 mm, at least about 5 mm, or at least about 1 cm. The first distance may be about 2.5 cm or less, about 2 cm or less, about 1.5 cm or less, or about 1.25 cm or less. In embodiments, the first distance is at about 1.5 times greater, about 1.75 times greater, about 2 times greater, or about 4 times greater than a width, e.g., a maximum width, of the groove. The first distance may be about 25 times greater or less, about 20 times greater or less, about 15 times greater or less, or about 10 times greater or less than a width, e.g., a maximum width, of the groove.
Also disclosed is a microfluidic pump module (100) utilizing the microfluidic structure described herein. Again with reference to
Also disclosed is a microfluidic device (100) utilizing the microfluidic pump module described herein. Again with reference to
Also disclosed is a microfluidic device (100), which again with reference to
In various embodiments, the flexible layer (10) comprises a raised element (30) disposed over a portion or all of the microchannel (40). The raised element (30) provides an increased cross-section thickness in the area which coincides with the microchannel (40). This assists in creating a water tight seal between the deformed elastomeric material (60) advanced into the microchannel (40) with the surface of the microchannel. One skilled in the art would understand that the raised element (30) may be one of a number of suitable shapes such as a bump. In other embodiments, the flexible layer (10) has no raised element (30), in which case microchannel (40) is covered entirely by flexible layer (10) which has a flat upper surface profile, which surface is not in contact with rigid substrate (20).
One or more microchannels (40) may be formed on a surface of the rigid substrate (20) by any number of suitable techniques known in the art. For example, microchannels may be formed by deposition of materials through a mask, chemical etching, laser etching, molding of a plastic substrate, and the like. A fluid tight seal is also formed between the rigid substrate (20) and the flexible layer (10) along a periphery of the microchannel (40) forming an enclosed capillary having a defined fluid flow path.
Microchannels may be dimensioned to define the volume within the microchannel and resultant flow rate for a given rate at which the elastomer is progressively deformed into the microchannel. The high quality and precision of the so formed microchannel results in a microfluidic pump element that can achieve very slow and consistent flow rates, which may not otherwise be achieved if alternate processes of manufacture were employed. A microchannel may be dimensioned such that it has a constant width dimension and a constant depth dimension along all or a portion of its length. In one embodiment, a microchannel will have a constant width dimension and a constant depth dimension along a length of the microchannel which engages a deformation element. In general, a microchannel has a width dimension of between 500 to 900 microns and a depth dimension of between 40 to 100 microns. As such, the device may be adapted for a flow rate within the microchannel of between 0.001 µl/s to 5.0 µl/s.
Microchannels having a variety of cross-sectional geometries may be utilized.
One skilled in the art would appreciate that the surfaces of microchannels (40) may be modified, for example by varying hydrophobicity. For instance, hydrophobicity may be modified by application of hydrophilic materials such as surface active agents, application of hydrophobic materials, construction from materials having the desired hydrophobicity, ionizing surfaces with energetic beams, and/or the like.
As discussed herein, a device of the present invention may include a plurality of microchannels (40), each having various geometries and disposed on the rigid substrate (20) (or in the alternate on the flexible layer (10)) in a variety of patterns. For example, microchannels (40) may be linear or extend arcuately along the surface of the rigid substrate (20).
A spiral or generally circular shaped microchannel allows for fluid to be advanced through the microchannel of the pump module or device by a deformation element (50) that is radially coupled to the device.
Housing (80) may be rotated by applying a voltage to a motor controlling movement thereof. As such, also disclosed is a method for performing a microfluidic process which includes applying a voltage to a device as described herein. The applied voltage activates a motor which advances at least one deformation element (50), such as one or more rollers, which are rotatably engaged with the elastomeric first plate element (10), causing deformation of a raised element (30) on the flexible layer (10) into the microchannel (40) formed on the surface of the rigid substrate (20).
A wide range of pulses per second may be applied to the electrical motor thereby effectuating a wide range of flow rates within microchannels. The fluid flow is essentially constant, with little or no shear force being imposed on the fluid, even at very low flow rates. These characteristics of the pump enhance the accuracy of analyses performed with it (e.g., analyte integrity is preserved by minimizing exposure of sample components to shear and degradation), while low flow rates provide sufficient time for chemical reactions to occur. A low, constant pumped flow rate can also be very useful in drug delivery, to ensure dosing accuracy.
In one embodiment, between 100 and 10,000 pulses per second may be applied resulting in a flow rate of between 0.001 µl/s to 5.0 µl/s through microchannels. The design of the present invention allows forces within microchannels of the present invention to remain fairly constant over a wide range of applied pulses.
For example,
With reference to
A variety of methods may be utilized to couple rigid substrate (20) to the elastomer that forms flexible layer (10). The parts may be joined together using UV curable adhesive or other adhesive that permits for movement of the two parts relative one another prior to curing of the adhesive/creation of bond. Suitable adhesives include a UV curable adhesive, a heat cured adhesive, a pressure sensitive adhesive, an oxygen sensitive adhesive, and a double-sided tape adhesive.
Alternatively, the parts may be coupled utilizing a welding process. Such processes including an ultrasonic welding process, a thermal welding process, and a torsional welding process.
In a further alternative, the parts may be joined using a process of two-shot molding or overmolding, in which case first one polymer and then the other is injected into a mold tool. One of skill in the art will readily appreciate that elastomeric and non-elastomeric polymers can be joined in this way to achieve fluid tight seals between the parts.
A process of laser welding may be utilized. The process includes:
The benefits of such approaches mean that (i) the parts may be manipulated (slid against one another) during manufacture to achieve desired alignments, (ii) intricate forms can be achieved in the non-elastomer - linear or arcuate channels (or combinations thereof) with a plurality of channel geometries, (iii) connections with the device may be made via the non-elastomeric material, which is dimensionally stable.
In various embodiments, additional microchannels and structures may be provided to allow the device to perform a number of different types of biological assays or reactions. For example, additional fluid or reagent reservoirs may be provided, one or more of which act as a reaction chamber for example. Additional structure and depicted in the following example which is intended to illustrate but not limit the invention.
The following embodiment describes the use of a planar circular or spiral peristaltic pump of the present invention for use in low cost diagnostic products consisting of an instrument and consumable, where the consumable requires sealing due to a potential high risk of contamination.
Two aspects are described. First, a very low cost method to perform pumping a liquid sample to stored dry chemicals which are deposited at a location internal to the consumable, followed by mixing of the liquid sample with the stored chemicals. Second, dilution of chemicals using the same active pumping system where the dilution step occurs part way through the diagnostic process.
The two aspects may be used together or individually. They shall now be described separately with reference to
With reference to
By providing inlet and outlet ports to the mixing chamber from the pump microchannels, the pump and mixing chamber are fluidically connected, thus fluid can be pumped from the pump microchannels into the mixing chamber as the motor rotates in a predetermined direction. The instrument component of the pump comprises a suitable mechanism to provide pumping and mixing functionality when the motor is rotated in a certain direction, but only mixing functionality when the motor is rotated in the opposite direction, for example a ratchet system implemented by a pawl (10) and a compression spring (11) whereby the mixing head rotates with the pump rollers in one rotational direction of the motor and whereby the pump rollers disengage from the motor when the motor rotates in the other direction, thus providing rotation of the mixing head only. The compression spring may also provide the necessary contact force on the pump channels to facilitate effective pumping. A sequence of events is provided in Table 1 below.
Another embodiment provides an annular mixing chamber internal or external to the pump channels. This embodiment could feasibly be produced at a lower cost than the first embodiment and is described with reference to
Located within this annular channel is one or many bearing balls (5) which are magnetically coupled to a magnetic or magnetized element on the rotor (6) such that as the rotor rotates the bearing balls also rotate in the annular channel, thus providing mixing of chemicals initially deposited inside the annular channel. The drive mechanism to achieve mixing and pumping in one rotational direction of the motor and just mixing in the other rotational direction of the motor is envisaged to be similar to that described with reference to
With reference to
Should more fluids be required to be pumped in separate channels, this peristaltic pump can be designed to accommodate multiple fluidic channels on different radii if desired. In this embodiment the sample that is transported is first required to be mixed with stored deposited chemicals (6) located within the mixing chamber (7), followed by a dilution step using a dilution fluid.
It is preferable to store the dilution fluid away from the stored chemicals so the stored chemicals do not become affected by the dilution fluid. When the motor rotates in a certain direction the pump rollers engage with the pumping membrane to transport both sample fluid and dilution fluid into the consumable, as the mixing chamber fills with sample fluid, the dilution fluid fills a secondary chamber (8) which is sized according to the amount of dilution fluid required and the geometry of the dilution fluid pumping channels and the mixing chamber volume. When the motor stops both dilution fluid and sample fluid remain in their respective chambers.
If mixing is required, an equivalent mechanism as described above could be implemented which rotates the motor in the opposite direction to only provide mixing. When the sample fluid and dilution fluid are required to be combined, the motor rotates to engage the pump rollers which transport the sample and dilution fluid to a location inside the consumable which combines the two fluids (9). To assist combining the two fluids, passive mixing features (10) may be included at the fluid combining region. As the motor continues to rotate to pump the two fluids, the diluted sample can be transported to another location on the consumable, for example a location to carry out detection of an analyte (11).
Several advantages are provided by the invention. First, manufacturing costs are lowered due to the function and form of the circular or spiral peristaltic pump design. Aspects of the pump design which make this possible are circular or spiral geometry allows for the use of only one actuator; in this embodiment it is an electric motor, such that rotating the motor in one direction performs a different function to rotating the motor in the opposite direction. An additional feature of the pump design is the ability for the consumable part of the pump to include multiple pump channels such that multiple fluids may be transported using the same motor drive mechanism.
If a chemical reaction, such as an amplification reaction, is performed which could result in contamination, or if the potential for contamination is to be removed for other reasons, then the pump design allows the pump to be sealed to the environment.
A wide range of pulses per second may be applied to the electrical motor thereby effectuating a wide range of flow rates within microchannels, including very low flow rates. The fluid flow is essentially constant, with little or no shear force being imposed on the fluid, even at very low flow rates. These characteristics of the pump enhance the accuracy of analyses performed with it (e.g., analyte integrity is preserved by minimizing exposure of sample components to shear and degradation), while low flow rates provide sufficient time for chemical reactions to occur. A low, constant pumped flow rate can also be very useful in drug delivery, to ensure dosing accuracy.
Although the invention has been described it will be understood that modifications and variations are encompassed within the scope of the invention. Accordingly, the invention is limited only by the following claims.
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.