Patent Application
20240181452
The present invention relates to a microfluidic system for compensation of evaporation of liquid from channels. The present invention further relates to a diagnostic device comprising the microfluidic system.
Microfluidic systems, such as micro-total analysis systems, and miniaturized point-of-care devices have gained increasing interest over the last decades. Such systems typically may involve benefit including rapid analysis response at the point of sampling and enabling analysis even away from analytical laboratories or hospitals. Microfluidic systems and point-of-care devices may be used in analysis of biological samples or liquids, such as blood samples, including whole blood.
Analysis, handling and treating of liquid samples, such as aqueous samples, for example blood samples, in miniaturised systems is troublesome since liquids normally evaporates quickly when exposed to air. Such evaporation may lead to failure in microfluidic systems. For example, air entering microfluidic channels can result in termination of flows and/or disturbance in detection. Further precipitation or even crust formation may occur in samples subjected to evaporation, which may be particularly problematic for biological samples such as blood samples. Other problems associated with evaporation from samples, and particularly for the minute sample volumes often associated with microfluidic systems may be a reduced sample volume, which may result in decreased accuracy of, or even erroneous, analytical results, particularly so if the expected accuracy of analysis depends on a precisely measured sample volume.
Solutions to overcome problems associated with evaporation of sample liquid include avoiding of evaporation by saturation of surrounding air with liquid, or isolating the sample liquid from ambient air. However, such solutions suffer from being difficult to control and not viable for easy-to-use point-of-care devices, in particular for use under varying conditions or environments.
There is, thus, a need to provide microfluidic systems with reduced problems associated with evaporation of liquid from the systems, not just concerning blood samples, but many type of liquid samples or samples in solution.
It is an object to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solve at least one above indicated problem.
According to a first aspect of the present inventive concept, there is provided a microfluidic system for compensation of evaporation of liquid from channels. The microfluidic system comprises: a compensating microfluidic channel having a first end arranged for hindering capillary driven flow of a liquid out from the compensation microfluidic channel via the first end, and, a second end, being connected to a first microfluidic channel; a sample manipulation portion comprising a plurality of outlet channels, wherein each outlet channel ends in a respective stop valve, wherein the first microfluidic channel connects to the sample manipulation portion, thereby being in fluidic connection with the plurality of outlet channels, wherein each outlet channel of the plurality of outlet channels is arranged to exert a retention capillary pressure on the liquid, wherein the compensating microfluidic channel is arranged to exert a retention capillary pressure on the liquid, wherein the retention capillary pressure of each outlet channel is larger than the retention capillary pressure of the compensating microfluidic channel, such that the liquid flows from the compensating microfluidic channel towards the sample manipulation portion if liquid evaporates from one or more of the plurality of outlet channels at the respective stop valve, thereby compensating for evaporation of the liquid from the plurality of outlet channels at the respective stop valve.
By means of the present microfluidic system, evaporation from openings, such as capillary stop valves, may be compensated by liquid from a compensating channel. Thereby, air intrusion at openings, such as at stop valves, can be avoided, and interruption or termination of capillary flows can be avoided or mitigated. With the present microfluidic system evaporation from openings may be compensated for passively, i.e. without need of pumps or intervention by a user of the system. It is further beneficial with the present inventive concept that evaporation from anywhere in the microfluidic system may be compensated for. For example, it may relate to openings towards the aimbient surroundings outside of the system, or it may relate to any interface with gaseous medium, for example within the system, such as, for example, at a capillary trigger valve, which may be the case where one of the stop valves is a capillary trigger valve.
According to a second aspect of the present inventive concept there is provided a diagnostic device comprising the microfluidic system of the first aspect.
According to a third aspect of the present inventive concept there is provided a method for compensating evaporation of liquid from channels in a microfluidic system. The method comprises: providing liquid to a sample inlet of a second microfluidic channel, whereby the second microfluidic channel draws liquid, by capillary action, from the sample inlet to fill the second microfluidic channel; drawing liquid, by capillary action, from the second microfluidic channel into a compensating microfluidic channel and a first microfluidic channel, the compensating microfluidic channel and the first microfluidic channel branching off from the second microfluidic channel; drawing liquid, by capillary action, from the first microfluidic channel into a plurality of outlet channels of a sample manipulation portion, wherein each outlet channel ends in a respective stop valve; halting the liquid at the respective stop valve; wherein the compensating microfluidic channel exerts a retention capillary pressure on the liquid, and wherein each outlet channel of the plurality of outlet channels exerts a retention capillary pressure on the liquid, each retention capillary pressure of the plurality of outlet channels being larger than the retention capillary pressure of the compensating microfluidic channel; and flowing liquid from the compensating microfluidic channel towards the sample manipulation portion in response to liquid evaporating from one or more of the plurality of outlet channels at the respective stop valve, thereby compensating for evaporation of the liquid from the plurality of outlet channels at the respective stop valve.
The method according to the third aspect may be implemented using a microfluidic system according to the first aspect and embodiments thereof. References to the first aspect and embodiments are hereby made.
The above and other aspects of the present inventive concept will now be described in more detail, with reference to appended drawings showing variants of the invention. The figures should not be considered limiting the invention to the specific variant; instead they are used for explaining and understanding the inventive concept.
As illustrated in the figures, sizes of components, such as channels, and regions may be exaggerated for illustrative purposes and, thus, be provided to illustrate the general structures of variants of the present inventive concept. Like reference numerals refer to like elements throughout.
The present inventive concept will now be described more fully hereinafter with reference to the accompanying drawings, in which variants of the inventive concept are shown. The inventive concepts may, however, be implemented in many different forms and should not be construed as limited to the variants set forth herein; rather, these variants are provided for thoroughness and completeness, and fully convey the scope of the present inventive concept to the skilled person.
It is to be understood that at least the first microfluidic channel, the second microfluidic channel, the compensating microfluidic channel and the outlet channels are capillary channels. A capillary channel is a channel capable of providing a capillary-driven flow of a liquid. It is also to be understood that other channels and components of the system may be capillary channels and/or other types of channels depending on the specific implementation of the present inventive concept. Although a capillary channel is capable of providing a capillary-driven flow of a liquid, it is not excluded that other types of transport or forwarding of liquids may be used with the microfluidic channels. For example, pressure-assisted flows may be employed.
In the following, liquid may flow through channels and reach certain positions at different times within the microfluidic system. Flow rates of flows may be controlled in different manners in order for the fluid to reach the positions at the described times. A capillary-driven flow of a fluid requires one or more contacting surfaces that the fluid can wet. For example, surfaces comprising glass or silica may be used for capillary-driven flows of aqueous liquids. Further, for example, suitable polymers with hydrophilic properties, either inherent to the polymer or by modification, including for example chemical modification or coating, may promote or enhance capillary driven flows. Capillary-driven flows, in addition to being dependent on materials of surfaces, is dependent on the liquid flowing. Attractive forces between the liquid and surfaces of channels have effect on a capillary-driven flow.
Further, capillary-driven flows may be controlled, for example, by adapting dimensions, including length, width and depth, of the channels and/or by adapting the flow resistances of the channels, and/or by adapting capillary driving forces or pressures. For example, the flow resistance of a channel may be controlled by adapting a cross-sectional area of the channel and/or the length of the channel. The flow resistance of a channel may, as indicated above, further be dependent on properties of the liquid, e.g. its dynamic viscosity. Additionally, or alternatively, the flow rate may be adapted by using flow resistors, for example flow resistors in a flow path of the liquid. A flow resistor may be a channel with a defined flow resistance in a flow path of the liquid.
To provide desired capillary forces, dimensions of flow channels may be selected dependent on, for example, the liquid and properties of the liquid and/or material and/or properties of walls of the channels.
Capillary pressure may be generated when an interface is present between two fluids and is a function of the geometry of the channel, the surface properties and the two fluids. Capillary pressure, such as retention capillary pressure may be determined, for example by calculation. As one example, a capillary pressure in a rectangular cross section channel may be calculated for a liquid according to equation (1):
wherein γ is the surface tension coefficient of the liquid with a gas phase, for example about 0.072 N/m for water with air, wc is the channel width, hc is the channel height, and Θ is the contact angle of the liquid with the solid surfaces of the channel, for example, <90° for a hydrophilic material.
For example, water flowing in a 50 μm by 50 μm cross section channel with a contact angle of 45° yields a capillary pressure of about 4.1 kPa.
Typically, during normal use of a capillary channel or microfluidic channel of a system, the channel will be filled with liquid to a point where capillary driven flow of the liquid stops, i.e. often all the way up to the end of the respective channel, when liquid is dispensed in the system. The liquid may stop before reaching the end of the channel, such as if a portion of the channel has properties which stops the capillary driven flow before reaching the end of the channel. If no pull due to evaporation, the interface will stay flat where the capillary driven flow of the liquid stopped, eg. at the end of the channel. If a pull due to evaporation and if no liquid is available to refill the channel the interface will curve and start to recede in the channel. As used herein, retention capillary pressure may be described as the pressure necessary to create a receding interface that will move in a direction from the point where capillary driven flow of the liquid stopped towards a position from which the liquid came.
This retention capillary pressure may depend on the dimensions/geometries of the channel and/or and properties of the liquid and/or material and/or properties of the walls of the channels. For example, a (rectangular) channel with constant cross-section and surface properties of the walls along its length will have constant retention capillary pressure along its length for a given liquid. For example, a (rectangular) channel with constant cross-section and with sections with different surface properties of the walls along its length will have different retention capillary pressures for a given liquid in each of the sections.
With reference to
Each outlet channel 22, 24 of the plurality of outlet channels 22, 24 may be arranged to exert a retention capillary pressure on the liquid at, or adjacent to, the end, or at the stop valve, of each and respective outlet channel 22, 24.
The compensating microfluidic channel 10 may be arranged to exert a retention capillary pressure on the liquid at the first end 14.
The compensating microfluidic channel may have a capillary stop portion arranged at the first end for hindering capillary driven flow of a liquid out from the compensation microfluidic channel via the first end. The capillary stop portion may be, for example, a capillary stop valve. Thus, for example, the first end 14 of the compensating microfluidic channel 10, 101 may be connected to a capillary stop valve, thereby arranged for hindering capillary driven flow of a liquid out from the compensation microfluidic channel 10 via the first end 14.
With considerations to the illustrated microfluidic system 1, assumed for the discussion herein below to have the microfluidic channels filled with liquid (not illustrated) such as aqueous liquid. If evaporation of the liquid occurs from one or more of the stop valves 26, 28 there will be exerted a capillary pressure at the one or more stop valves 26, 28 which is larger than the retention capillary pressure of the compensating microfluidic channel 10, on the liquid, which will result in liquid flowing from the compensating capillary channel 10 towards the one or more stop valves. This is a result of the retention capillary pressure of each outlet channel 26, 28 being larger than the retention capillary pressure of the compensating microfluidic channel. Thereby, entry of fluid or gas, such as air, ambient to the stop valves 26, 28 as replacement for liquid being evaporated can be avoided as a result of liquid from the compensating microfluidic channel 10 flowing towards the stop valves 26, 28. Ambient fluid, such as air, will instead enter the system 1 via the first end 14 at the compensating microfluidic channel 10 and replace void from liquid evaporated from the one or more stop valves 26, 28. Thereby, air bubbles can efficiently be avoided at the one or more outlet channels 22, 24, and thereby air bubbles can be avoided to enter the system 1 outside of the compensating microfluidic channel, and/or disturb capillary flows at the one or more stop valves 26, 28.
The first end 14 of the compensating microfluidic channel 10 being arranged for hindering capillary driven flow of a liquid out from the compensation microfluidic 10 channel via the first end 14, may be realized for example by the compensating microfluidic channel 10 mouthing into a larger and/or deeper non capillary pressure generating portion. For example, mouthing into, or being connected to, a sample or buffer liquid reservoir. The compensating microfluidic channel may also be simply a cut of microfluidic capillary tubing or arranged in another fashion to stop capillary flow out from the first end 14.
The outlet channels 22, 24 have been schematically illustrated as having smaller dimensions as compared to the compensating microfluidic channel 10, which may be one way of providing the desired retention capillary pressures. It will be appreciated that the channels may have similar dimensions over a major portion of the capillary lengths, but that the terminating portions of the outlet channels 22, 24 may be eg. narrower, thus exerting or providing larger capillary pressures as compared to the compensating microfluidic channel 10. It shall be realized and appreciated, that other properties than channel dimensions may have an effect on capillary retention pressures, such eg. properties relating to the liquid, or materials of channel walls, to mention some examples. For example, the outlet channels 22, 24 may be fabricated from more hydrophilic material as compared to the material of the compensating microfluidic channel 10.
The sample manipulation portion 20 may comprise any suitable type of sample manipulation, including, for example, sample transport, sample metering, sample manipulation by reaction, sample sorting or sample analysis. Thus, sample manipulation, as used herein, may, for example, involve forwarding of a liquid or sample in the sample manipulation portion 20, such as by capillary driven flowing. The sample manipulation does not have to, although it may, involve transformation, such as via reaction, of the sample.
The microfluidic system may function with other type of liquids than sample liquid.
Suitable dimensions of microfluidic channels and outlet channels of the system may be selected. Typical cross-sections of channels, as seen along a flow direction of the channel, will now be exemplified. For example, eg. concerning a channel having a rectangular cross-section, cross-sections of the microfluidic channels and outlet channels may have a dimension, such as a height of a channel, between 5 μm and 3 mm, and may have another dimension, such as a width of a channel, between 5 μm and 3 mm. The cross-section may have any suitable shape, for example a circular cross-section, which may have a dimension, or a diameter, between 5 μm and 3 mm. If a channel has a rectangular cross-section, one dimension, such as a height of the cross-section may be selected to provide capillary driven flow, such as having a dimension of, for example, 5 μm to 1 mm, while the other another dimension of the cross-section may be selected being larger, such as, for example, having a dimension between 1 and 3 mm. Lengths of channels may be selected to suit its purpose. Typical lengths may be, for example, from 10 μm and up to 1 meter, such as from 10 μm to 10 mm.
The compensating microfluidic channel may comprise a sample inlet at the first end. For example, a microfluidic system 1 as illustrated and discussed with reference to
The liquid and/or sample liquid may be aqueous liquid, for example a solution in water.
With reference to
Hindering capillary driven flow of liquid out from the second microfluidic channel 30 via the sample inlet 32 may be realized, for example, by a capillary stop valve, or other means of terminating capillary driven flows, such as according to examples described herein. Thus, the sample inlet 32 may be connected to a capillary stop valve, thereby arranged for hindering capillary driven flow of liquid out from the second microfluidic channel 30 via the sample inlet 32. As an alternative to a capillary stop valve, another non capillary pressure generating portion may be connected to the sample inlet 32. For example, this may be realised by the sample inlet 32 mouthing into a wider, thus capillary driven flow terminating, portion, such as, for example, by being connected to or mouthing into a liquid reservoir or well, such that capillary driven flow out of the sample inlet 32 is prevented or hindered.
When the microfluidic system 1 further comprises the second microfluidic channel 30, the second microfluidic channel may be arranged to exert a first retention capillary pressure on the liquid, and the first retention capillary pressure may be larger than the retention capillary pressure of the compensating microfluidic channel. Thereby, the liquid may flow from the compensating microfluidic channel 10 towards the second microfluidic channel 30 if the liquid evaporates from the sample inlet 32, thereby compensating for evaporation of the liquid from the second microfluidic channel 30 at the sample inlet 32.
An example or embodiment of the microfluidic system 1 illustrated with reference to
Now it shall be discussed and considered that the retention capillary pressure of each outlet channel 22, 24 and the first retention capillary pressure of the second microfluidic channel, may be larger than the retention capillary pressure of the compensating microfluidic channel. Thereby, if liquid is evaporated from any of the sample inlet 32 of the second microfluidic channel 30, and the stop valves 26, 28 of the outlet channels 22, 24, liquid bulk will be retained at those positions while losses resulting from evaporation will be compensated for by a flow of liquid from the compensating microfluidic channel 10, since the retention capillary pressure of the compensating microfluidic channel is lower than the retention capillary pressures of each outlet channel 22, 24. Thereby evaporation of the liquid from the sample inlet, and capillary stop valves (26, 28) will be compensated for. Any air pockets or air bubbles from evaporation will be comprised by and concentrated to the compensating microfluidic channel 10.
For some exemplary embodiments or examples, liquids termed ‘sample liquid’ or ‘liquid’ is described to be contained within the microfluidic system. Although it may be that one type of liquid is contained within the microfluidic system, alternatively several liquids or type of liquids may be contained within the microfluidic system. For example, one or more portions of the microfluidic system, such as channels or parts of channels, may be filled with eg. sample liquid and other one or more portions, such as channels or parts of channels, may be filled with other liquid, such as buffering liquids or other sample liquids. It may be desirable and even preferred for some applications that all liquid within the system is of similar type or have similar capillary pressure properties. For example, different liquids within the microfluidic system may be aqueous liquids, such as diluted water solutions associated with similar capillary force.
The microfluidic system, for example, as discussed with reference
Sample manipulation may be forwarding, without further manipulation or treatment, sample liquid to one or more of the outlet channels 22, 24 and the stop valves 26, 28
The plurality of outlet channels may comprise a first outlet microfluidic channel ending in a first stop valve, and a second outlet microfluidic channel ending in a second stop valve; wherein the first outlet microfluidic channel is arranged to exert a second retention capillary pressure on the liquid, and the second outlet microfluidic channel is arranged to exert a third retention capillary pressure on the liquid; wherein the second retention capillary pressure is larger than the retention capillary pressure of the compensating microfluidic channel, such that the liquid flows from the compensating microfluidic channel towards the first outlet microfluidic channel, if liquid evaporates from the first outlet microfluidic channels at the first stop valve, thereby compensating for evaporation of the liquid in the first outlet microfluidic channel at the first stop valve, and wherein the third capillary pressure is larger than the retention capillary pressure of the compensating microfluidic channel, such that the liquid flows from the compensating microfluidic channel towards the second outlet microfluidic channel, if liquid evaporates from the second outlet microfluidic channels at the second stop valve, thereby compensating for evaporation of the liquid in the second outlet microfluidic channel at the second stop valve.
A cross sectional area of the compensating microfluidic channel may be between 1.1 and 10, such as between 1.1 and 4 times, larger than a cross sectional area of the first outlet microfluidic channel adjacent to the first stop valve; and a cross sectional area of the compensating microfluidic channel may be between 1.1 and 10, such as between 1.1 and 4 times, larger than the cross sectional area of the second outlet microfluidic channel adjacent to the second stop valve. This may be one way of realizing the lower retention capillary pressure associated with the compensating microfluidic channel. It shall be realized and appreciated that other ways or means may be relevant in addition to or as alternatives to providing those relations between cross sectional areas. For example, the material or surface properties of the channels may be selected to provide desirable capillary pressures. To mention one example, the compensating microfluidic channel may have walls manufactured from or coated with material or compounds providing a lower capillary pressure of the liquid within. For example, the walls may have more hydrophobic properties than walls of the outlet channels or the second channel, optionally in combination with variations in cross-sectional areas. The compensating microfluidic channel may even have narrower dimensions, or a smaller cross-section, as compared to the outlets or channels adjacent to the outlets, if eg. properties still realize the lower retention capillary pressure associated with the compensating microfluidic channel.
Typically, the microfluidic system is intended to be used with the microfluidic channels filled with the liquid, and evaporation from the stop valves 26, 28 and optionally at sample inlet is compensated for via fluid from the compensating microfluidic channel 10. The retention capillary pressures of each of the outlet channels 22, 24 and of the second microfluidic channel may be determined by the retention capillary pressure at the end/outlet portions of the, respective, channel. For example, one or more of outlet channels and 22, 24 and second microfluidic channel 30 may be capillary channels being relatively wide but having a narrowing at the ends or at the inlet, thus providing or exerting relatively high retention capillary pressures when filled with liquid as compared to the retention capillary pressure of the compensating microfluidic channel, even though their dimensions may be eg. similar or larger over a major portion of the capillaries. The outlet channels and 22, 24 and second microfluidic channel 30 may also be described as channels having identical or similar cross-sectional areas over the length of the channel, thus having capillary pressure inside the channel similar to the pressure at the end portion.
The compensating microfluidic channel 10 may have a constant cross-sectional area as seen in a direction of the channel towards first end 14, or be adapted to exert a constant capillary pressure on the liquid, over a large or full length of the compensating microfluidic channel. Thereby, the compensating microfluidic channel may compensate for larger evaporation losses from eg. the stop valves or inlets and be less independent of the position of the liquid/gaseous interface within the compensating microfluidic channel. However, to provide compensation for less evaporation it may be sufficient that the compensating microfluidic channel has a cross-sectional area, or be adapted otherwise, at, or adjacent to, the first end 14 of the compensating microfluidic channel.
For example, the compensating microfluidic channel 10 may have a widening or enlarged cross-sectional area as seen in a direction of the channel towards the first end 14 of the compensating microfluidic channel while realizing the provision that the retention capillary pressure of each outlet channel 22, 24, and, where relevant, the second microfluidic channel, being larger than the retention capillary pressure of the compensating microfluidic channel. Such a compensating microfluidic channel 10, may however have a more limited compensating capacity than a similar channel without the widening or enlarged cross-sectional area, as the retention capillary pressure of the compensating microfluidic channel may increase and approach the retention pressures of the outlet channels 22, 24, as the level of liquid within the compensating microfluidic channel decreases.
The microfluidic system, when it is comprising a sample inlet, may further comprise a sample reservoir arranged for receiving sample fluid, wherein the sample reservoir is connected to the sample inlet. The sample reservoir may be configured essentially not to have a capillary action on liquid at the inlet.
The compensating microfluidic channel may be made of a first material, the first outlet microfluidic channel may be made of a second material, and the second outlet microfluidic channel may be made of the second material.
Thereby, capillary pressures may be designed or manipulated by selecting suitable first and second materials.
According to a second aspect of the present inventive concept there is provided a diagnostic device comprising the microfluidic system of the first aspect.
The diagnostic device may be arranged to analyse the sample liquid.
Benefits with the microfluidic system 1, 97, 99 will now further be discussed in view of exemplary embodiments, and with reference to
Now turning to
With reference to
The comparative system 98 illustrated and discussed with reference to
With reference to
With reference to
The second microfluidic channel 30 may exert a first retention capillary pressure on the liquid, and the first retention capillary pressure may be larger than the retention capillary pressure of the compensating microfluidic channel 10, wherein the method further may comprise flowing liquid from the compensating microfluidic channel 10 towards the second microfluidic channel 30 in response to liquid evaporating from the sample inlet 32, thereby compensating for evaporation of the liquid from the second microfluidic channel 30 at the sample inlet 32.
It shall be realized and appreciated, that the term outlet microfluidic channel as used herein refers to liquid being outlet from the sample manipulation portion (20), for example, as described in examples herein, but that the liquid may proceed to further manipulation or treatment, eg. analysis, or may be eg. discarded, or forwarded to an additional system.
The stop valves may be trigger valves, for example capillary trigger valves. Trigger valves may be understood as microfluidic structures comprising a fluidic junction of channels where a liquid flow from one channel is stopped at the junction and later may be triggered to flow by a liquid flow reaching the trigger valve or junction from another channel connected to the junction. The liquid flow from the one channel may be stopped at the junction for example, by having its outlet of the junction on the side wall of the another channel, which another channel is deeper than the one channel at the junction.
| Number | Date | Country | Kind |
|---|---|---|---|
| 21169487.2 | Apr 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/060421 | 4/20/2022 | WO |
