Patent Grant
11806709
The present invention concerns an interface component which is suitable for cooperating with a microfluidic device which can be used to extract ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles from a sample. There is further provided corresponding assemblies and a corresponding method of extracting ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles from a sample.
Existing techniques of extracting ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles from a sample involve moving said particles laterally, using a magnetic field, from the sample into a buffer solution. Specially sample and buffer solutions flow simultaneously along a channel of a microfluidic device; the channel of a microfluidic device has a planar channel bed (e.g. the channel has a rectangular cross section), and the particles are moved from the sample into the buffer solution, in a direction which is parallel to the planar channel bed. In some cases the channel of the microfluidic device has a curved channel bed in which case the particles are moved in a direction which is parallel to a tangent to the apex of the curve of the channel bed. However existing solutions for extracting ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles from a sample suffer from low throughput.
Also magnetic field which is used to move the particles from the sample into a buffer solution is provided by magnetized or magnetizable structures which are integral to the microfluidic device. Having magnetized or magnetizable structures integral to the microfluidic device increases the manufacturing costs of the microfluidic device. In order to be able to move the particles parallel to the planar channel bed the magnetized or magnetizable structures need be precisely positioned in the microfluidic devices so that their magnetic field gradient is parallel to the planar channel bed. In practice, the size of the magnetized or magnetizable structures is proportional to the magnetic force that can be applied to the particles; therefore to ensure effective extraction of ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles from the sample into a buffer solution, large magnetized or magnetizable structures need to be integrated to the microfluidic device, which in turn increases the dimensions of the microfluidic device.
There is a need in the art to provide an interface component which can be used with a suitable microfluidic device which can achieve improved extraction ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles from a sample.
The present invention aims to obviate or mitigate at least some of the disadvantages associated with the existing solutions for extracting ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles from a sample.
According to one aspect of the present invention there is provided a microfluidic device comprising, a pallet, having a first surface and second, opposite, surface; the first surface having defined therein, a main channel, and one or more inlet subsidiary channels each of which is in fluid communication with the main channel at a first junction which is located at one end of the main channel, and corresponding one or more outlet subsidiary channels each of which is in fluid communication with the main channel at a second junction which is located an second, opposite, end of the main channel; wherein the depth of the one or more inlet subsidiary channels and the depth of the one or more outlet subsidiary channels is less than the depth of the main channel so that there is step defined at the first junction and at the second junction; the second, opposite, surface having defined therein a groove which can receive a means for generating a magnetic field, wherein the groove is aligned with, and extends parallel to, the main channel.
The depth of the one or more inlet subsidiary channels may be equal to the depth of the one or more outlet subsidiary channels.
Two inlet subsidiary channels may be provided, which are arranged to join the main channel at opposite sides of the main channel, at the first junction; and two outlet subsidiary channels may be provided which are arranged to join the main channel at opposite sides of the main channel, at the second junction.
Two inlet subsidiary channels may be provided and two outlet subsidiary channels may be provided, and wherein the lengths of the two inlet subsidiary channels are equal and the length of the two outlet subsidiary channels are equal.
The length of the main channel between the first junction and second junction may be equal to half the length of an inlet subsidiary channel.
Preferably the length of the main channel between the first junction and second junction may be between 1-50 mm. Most preferably the length of the main channel between the first junction and second junction is 20 mm.
The ratio between a width and depth of the main channel may be between 0.2 and 5.
The microfluidic device may further comprise a film which overlays the first surface so as to overlay the main channel, the one or more inlet subsidiary channels and the one or more outlet subsidiary channels, so as to confine the flow of fluids to within the respective channels. The film may be removably attached to the first surface.
The length of the groove may be equal to the length the length of the main channel.
The centre of the groove is aligned with the centre of the main channel.
The groove may have a tapered cross section.
The groove may have a tapered cross section with a rounded apex. The rounded apex of the groove may have a radius of curvature between 0.05 mm-0.5 mm. Preferably the rounded apex of the groove will have a radius of curvature of 0.2 mm.
The groove may have a tapered cross section with a planar base
For example the groove may have a cross section which has the shape of a truncated triangle.
The groove may have a v-shaped cross section.
The thickness of the pallet between the groove and main channel is between 0.01 mm-10 mm. Preferably the thickness of the pallet between the groove and main channel is between 0.15 mm.
The microfluidic device may comprise a buffer source reservoir which is arranged in fluid communication with the main channel, and which can hold a buffer liquid which is to be fed into the main channel.
The microfluidic device may comprise a sample source reservoir which is arranged in fluid communication with the one or more inlet subsidiary channels, and which can hold a sample liquid which is to be fed into the one or more inlet subsidiary channels.
The microfluidic device may comprise a buffer drain reservoir which is arranged in fluid communication with the main channel, and which can receive a buffer liquid which has flown along the main channel.
The microfluidic device may comprise a sample drain reservoir which is arranged in fluid communication with the one or more outlet subsidiary channels, and which can hold a sample liquid which has flown along the one or more outlet subsidiary channels.
The thickness of the pallet between the groove and main channel may be between 0.01-0.2 mm.
The pallet may be composed of transparent material.
According to a further aspect of the present invention there is provided a method of extracting ferromagnetic, paramagnetic and/or diamagnetic particles from a sample, the method comprising the steps of,
The step of applying a magnetic field to the sample may comprise, moving a means for generating a magnetic field into said groove of the pallet of the microfluidic device.
The step of applying a magnetic field to the sample may comprise, providing a magnetic field which moves said particles out of a sample into the buffer, in a direction which is, perpendicular a channel bed of the main channel if the channel bed in planar, or, perpendicular to a tangent to an apex of the channel bed of the main channel if the channel bed is curved.
The step of applying a magnetic field to the sample may comprise, providing a magnetic field which moves said particles out of a sample into the buffer, in a direction which is, both perpendicular to the direction of flow of the sample and buffer along the main channel and either, perpendicular a channel bed of the main channel if the channel bed in planar, or, perpendicular to a tangent to an apex of the channel bed of the main channel if the channel bed is curved.
The method may comprise the step of adjusting the flow rate of the sample and buffer so that the flow rates of the sample and buffer are equal along the main channel.
The method may comprise the step of adjusting the flow rate of the sample and buffer so that the ratio between flow rates of sample in the inlet subsidiary channels and buffer in main channel at the first junction is between 0.1-10. Most preferably said ratio is between 0.5-2. In one embodiment the flow rate of the sample is twice that of the buffer at the first junction. In another example the flow rate of the buffer is twice that of the sample at the first junction.
The method may comprise the step of adjusting the flow rate of the sample and buffer so that the ratio between flow rates of sample in the outlet subsidiary channels and buffer in main channel at the second junction is between 0.1-10. Most preferably said ratio is between 0.5-2. In one embodiment the flow rate of the sample is twice that of the buffer at the second junction. In another example the flow rate of the buffer is twice that of the sample at the second junction.
According to a further aspect of the present invention there is provided an assembly comprising a microfluidic device according to any one of the above-mentioned microfluidic devices, and a means for generating a magnetic field located in the groove of the pallet.
The means for generating a magnetic field may be a permanent magnet which has a triangular shaped cross section.
The means for generating a magnetic field may have a shape corresponding to the shape of the groove in the pallet.
The means for generating a magnetic field may extend over a length which is at least equal to the length of the main channel in the microfluidic device.
The means for generating a magnetic field is preferably arranged so that its magnetization is perpendicular to a planar channel bed of the main channel. The means for generating a magnetic field is preferably arranged so that its magnetization is perpendicular to a tangent to an apex of a cross section of the channel bed (e.g. when the channel bed of the main channel is curved; or when the channel has a v-shaped cross section)
The means for generating a magnetic field is preferably arranged so that its magnetization is perpendicular to the direction flow of the sample and buffer in the main channel.
The means for generating a magnetic field may has a tapered cross section.
The means for generating a magnetic field may has a tapered cross section with a rounded tip. The rounded tip of the means for generating a magnetic field may have a radius of curvature between 0.05 mm-0.5 mm. Preferably the rounded tip of the means for generating a magnetic field may have a radius of curvature of 0.2 mm.
The means for generating a magnetic field has a tapered cross section with a flat apex; For example the means for generating a magnetic field may have a cross section which has the shape of a truncated triangle.
The means for generating a magnetic field may have a triangular cross section.
The means for generating a magnetic field may have a constant cross sectional shape along a length which is equal to, or greater than, the length of the main channel.
The means for generating a magnetic field may be a permanent magnet.
According to a further aspect of the present invention there is provided an interface component, suitable for cooperating with a microfluidic device, the interface component comprising,
Preferably the interface component is suitable for cooperating with any of the above mentioned microfluidic devices.
The interface component may comprise at least four elements, and at least four outlets.
The aerosol filter may comprise hydrophobic material.
The aerosol filter may comprise pores having a size in the range 0.1-0.3 μm. Preferably the aerosol filter may comprises pores having a size 0.22 μm.
The interface component may further comprise one or more magnetic assemblies. Each of the magnetic assemblies may comprise a permanent magnet.
Each of the magnetic assemblies may comprise,
Preferably the interface component comprises a platform on which the one or more magnetic assemblies are supported and on which the one or more elements are supported. When the shaft is moved in the second direction the means for generating a magnetic field is moved in a direction which is away from the platform. When the shaft is moved in a first diction the means for generating a magnetic field is moved in a direction towards the platform.
Preferably the interface component comprises a plurality of magnetic assemblies arranged in a row on the platform. For example the interface component may comprise a four magnetic assemblies arranged in a row on the platform. Preferably a plurality of elements are located on one side of the row and a plurality of elements are located on the other side of the row.
The means or generating a magnetic field may have a tapered cross section.
The means for generating a magnetic field may has a tapered cross section with a rounded tip. The rounded tip of the means for generating a magnetic field may have a radius of curvature between 0.05 mm-0.5 mm. Preferably the rounded tip of the means for generating a magnetic field may have a radius of curvature of 0.2 mm.
The means for generating a magnetic field has a tapered cross section with a flat apex; For example the means for generating a magnetic field may have a cross section which has the shape of a truncated triangle.
The means for generating a magnetic field may have a triangular cross section.
The means for generating a magnetic field may have a constant cross sectional shape along a length which is equal to, or greater than, the length of the main channel.
The means for generating a magnetic field may be a permanent magnet. The permanent magnet may have a length which is between 1-50 mm. Preferably the permanent magnet has a length of 20 mm. Preferably the permanent magnet has a constant cross section along the whole length of the permanent magnet.
The shaft of the plunger may be connected to said means for generating a magnetic field by at least two pin members which pass through holes defined in the pallet of the interface component. The at least two ping will help to ensure that the means for generating a magnetic field is prevented from rotating around a longitudinal axis of the magnetic assembly.
According to a further aspect of the present invention there is provided an assembly comprising,
The assembly may further comprises a pneumatic system which is operable to provide a positive air flow. The assembly may further comprises a pneumatic system which is operable to provide a negative air flow.
The interface component may comprise a row of magnetic assemblies, and elements located on opposite sides of the row of magnetic assemblies. The elements located on one side of the row may be fluidly connected to a pneumatic system which is operable to provide a positive air flow; and the elements which are located on the other opposite side of the row may be fluidly connected to a pneumatic system which is operable to provide a negative air flow.
Each of the one or more outlets are arranged to be in fluid communication with a respective reservoir of a microfluidic device.
At least one outlet is in fluid communication with a sample source reservoir. An element which is in fluid communication with said at least one outlet is fluidly connected to a pneumatic system which is operable to provide a positive air flow.
At least one outlet is in fluid communication with a buffer source reservoir. An element which is in fluid communication with said at least one outlet is fluidly connected to a pneumatic system which is operable to provide a positive air flow.
At least one outlet is in fluid communication with a sample drain reservoir. An element which is in fluid communication with said at least one outlet is fluidly connected to a pneumatic system which is operable to provide a negative air flow.
At least one outlet is in fluid communication with a buffer drain reservoir. An element which is in fluid communication with said at least one outlet is fluidly connected to a pneumatic system which is operable to provide a negative air flow.
According to a further aspect of the present invention there is provided a method of extracting ferromagnetic particles from a sample, further comprising providing a microfluidic device according to any one of the above-mentioned microfluidic devices; providing a sample which comprises ferromagnetic, paramagnetic and/or diamagnetic particles into a reservoir of the microfluidic device; providing a buffer in a reservoir of the microfluidic device; providing a interface component according to any one of the above mentioned a interface component, in cooperation with the microfluidic device so that one or more of the outlets are arranged to be in fluid communication with a respective reservoir of the microfluidic device
According to a further aspect of the present invention there is provided a flow restrictor suitable for use in any of the above-mentioned interface components, the flow restrictor comprising,
Preferably the intermediate channel has a circular cross section and has a diameter which is between 1-100 μm.
Preferably the capillary member is composed of transparent material such as glass for example.
The flow restrictor may comprises a male member and female member which are configured so that they can mechanically cooperate with each other so that the male and female members can be fixed together;
The depth of the pocket in the male member is such that when the capillary member is positioned into the pocket such that capillary member abuts a base of the pocket, at least 0.5 mm of the length of the capillary member extends out of the pocket.
Preferably the depth of the pocket in the male member is between 0.5 mm-19.5 mm. Most preferably the depth of the pocket in the male member is 1.5 mm.
The pocket in the male member preferably has a circular cross section. The diameter of the pocket in the male member is preferably between 0.5 mm-5 mm.
Preferably the depth of the pocket in the female member is between 0.5 mm-20 mm. Most preferably the depth of the pocket in the female member is 5 mm.
The pocket in the female member preferably has a circular cross section. The diameter of the pocket in the female member is preferably between 0.5 mm-5 mm.
The capillary member may have length between 2.20 mm. Most preferably the capillary member has a length between 4-8 mm.
Preferably the length of the portion of the capillary member which is contained within pocket of the female member, is at least 0.5 mm.
The flow restrictor may further comprise an o-ring located at an interface between the male and female members.
The male member may further comprise an annular groove defined therein which can receive the o-ring.
The o-ring may be arranged to abut the male member, female member, and capillary member simultaneously.
The capillary member may extend through the o-ring.
The ratio of the cord thickness of the o-ring to the inner diameter of the o-ring may be between 0.1-1. Preferably the ratio of the cord thickness of the o-ring to the inner diameter of the o-ring is 0.5 or 0.8.
The inlet channel may have a circular cross section. The inlet channel may have a diameter in the range 0.2 mm-1.5 mm.
The outlet channel may have a circular cross section. The outlet channel may have a diameter in the range 0.2 mm-1.5 mm.
The male member may have an external tread, and the female has an internal thread or vice versa.
The male member may further comprise ribbing on an outer surface thereof. The female member may further comprise ribbing on an outer surface thereof.
According to a further aspect of the present invention there is provided a flow restrictor assembly which comprises,
The invention will be better understood with the aid of the description of an embodiment given by way of example and illustrated by the figures, in which:
Referring to
For each main channel 5 there is provided are two inlet subsidiary channels 6a,6b, each of which is in fluid communication with a respective main channel 5 at a first junction 7 which is located at the first end 5a of the respective main channel 5. Corresponding two outlet subsidiary channels 8a,8b each of which is in fluid communication with a respective main channel 5 at a second junction 9 which is located at the second, opposite, end 5b of the respective main channel 5. It will be understood that any number of inlet subsidiary channels and any number of outlet subsidiary channels may be provided for each main channel 5; however most preferably the number of inlet subsidiary channels will correspond to the number of outlet subsidiary channels. The two inlet subsidiary channels 6a,6b mirror one another, and the and two outlet subsidiary channels 8a,8b mirror one another.
A film 18, overlays the main channels 5, and the respective inlet subsidiary channels 6a,6b and outlet subsidiary channels 8a,8b so as to confine the flow of fluids to within the respective channels 5,6a,6b,8a,8b. The film 18 is removably attached to (or fixed to) the first surface 4a so that it can be selectively removed and attached to the first surface 4a. The film is composed of transparent material, such as transparent thermoplast, so as to allow a user to observe the flow of fluids within the microfluidic device
Referring to
The groove 15 is shown to be aligned with the main channel 5; in other words the centre of the groove 15 is aligned with the centre of main channel 5 as represented by axis 16. The width ‘w’ of the groove 15 tapers. Specifically, side walls 15a,15b defining the groove 15 are slanted so that width ‘w’ of the groove 15 tapers towards a surface 15c which defines a base of the groove 15. The thickness ‘t’ of the pallet 3 between the groove 15 and channel 5 is never below 0.01 mm, and is preferably 0.15 mm (or at least between 0.01-10 mm); more specifically along the axis 16 (on which the centre of the groove 15 and centre of main channel 5 lie) the thickness ‘t’ of the pallet 3 is between 0.01-10 mm, and is preferably 0.15 mm.
In this example shown in
As shown in
Briefly referring back to
Each main channel 5 is also fluidly connected, via a third conduit 13, to a respective buffer drain reservoir 107 (shown in
The microfluidic device 1 shown in
Each of the permanent magnets 20a-d is received into a respective groove 15 which is defined in the second surface 4b of the pallet 3. The cross section of each permanent magnet 20a-d has a shape corresponding to the shape of the cross section of the groove 15; thus in this example each permanent magnet 20a-d have a tapered width and each permanent magnet 20a-d also has a flat top surface 21 corresponding to the flat surface 15c which defines a base of the groove 15. It will be understood that if the cross section of the grooves 15 had a curved apex (i.e. a base surface 15c which has a curved profile), then each permanent magnet 20a-d would have a cross section with a correspondingly curved apex (in this case preferably each permanent magnet 20a-d would have a cross section would have an apex which has a radius of curvature between 0.05 mm-0.5 mm; and most preferably each permanent magnet 20a-d would have a cross section would have an apex which has a radius of curvature of 0.2 mm). Likewise if the grooves has a v-shaped cross section then the permanent magnets 20a-c would also be shaped to have a corresponding v-shaped cross section. By having the cross sectional shape of each permanent magnet 20a-d corresponding to the cross sectional shape of the grooves 15, allows the permanent magnets 20a-d to snugly fit into their respective grooves 15. Preferably the permanent magnets 20a-d will snugly fit into their respective grooves 15 so that the apex or top of each of the permanent magnets 20a-d abuts the surface 15c defining base of the respective groove 5 into which it is received; this ensures that there is no air gap between the permanent magnets 20a-d and the surfaces 15c defining base of the respective grooves 15.
Furthermore the length of each of the permanent magnets 20a-d corresponds to the length of the respective groove 15 into which it is received. Since in this example the length of the grooves 15 corresponds to the length of the main channels 5 between the first junction 7 and second junction 9, the length of each of the permanent magnets 20a-d will correspond to the length of the main channels 5 between the first junction 7 and second junction 9.
During use the permanent magnets 20a-d can provide a magnetic field within a respective main channel 5. Since each of the permanent magnets 20a-d have a length corresponding to the length of the main channels 5 between the first junction 7 and second junction 9, each of the respective permanent magnets 20a-d can generate a magnetic field which is constant along the length of a respective main channel between the first junction 7 and second junction 9.
The microfluidic device 1, as shown in
The sample which contains ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles is provided in a sample source reservoir 105. The sample flows from the sample source reservoir 105, via the second conduit 12, into the pair of inlet subsidiary channels 6a,6b. A buffer fluid, such as particle-free water is provided in a buffer source reservoir 106. The buffer fluid flows from the buffer source reservoir 106, via the first conduit 11, into the main channel 5. It will be understood that the buffer fluid may be any fluid which is absent of the particles which are to be removed from the sample (i.e. absent of the ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles which are to be removed); besides particle-free water other liquids such as phosphate buffer saline (PBS) solution or water containing a detergent may be used.
The sample flows along the inlet subsidiary channels 6a,6b and enters the main channel 5 at the first junction 7. Accordingly at junction 7 the main channel 5 will contain both the sample and buffer fluid so that both the sample and buffer fluid simultaneously flow along the main channel 5.
As can be seen in
A magnetic field is applied to the sample 30 and buffer 31 which are simultaneously flowing along the main channel 5. The magnetic field moves the ferromagnetic, paramagnetic (or super-paramagnetic), and/or diamagnetic particles contained within the sample 30 in both of the sample streams 30a, 30b into the buffer 31. In this example in order to apply a magnetic field to the sample 30 (and buffer fluid 31) which is flowing along the main channel 5, a permanent magnet 20a-d is moved into the groove 15 on the second surface 4b of the pallet 3, which is aligned with said main channel 5 in which the sample 30 and buffer 31 flow. The permanent magnet 20a-c has a magnetisation which is in a direction which is perpendicular to the direction of flow of the sample 30 and buffer 31 in the main channel 5, and is also perpendicular to the planar channel bed 5d of the main channel (or perpendicular to a tangent to the apex of the cross section of the main channel if the main channel has a curved channel bed or if the main channel 5 has a v-shaped cross section). It will be understood that any means for generating a magnetic field may be used to provide the magnetic field which is applied to the sample 30 and buffer 31; the present invention is not limited to requiring the use of a permanent magnet 20a-d. It is pointed out that by providing a permanent magnet 20a-d in the groove the assembly shown in
Advantageously, because buffer fluid 31 is interposed between each of the sample 30 and the channel bed 5d of the main channel 5, ferromagnetic, paramagnetic (or super-paramagnetic), and/or diamagnetic particles contained within the sample 30 can be moved from the sample 30 into the buffer fluid 31, in a direction which is perpendicular to, or substantially perpendicular to, the direction of flow of the sample streams 30a,30b and buffer fluid 31 in the main channel 5. More specifically ferromagnetic, paramagnetic (or super paramagnetic), and/or diamagnetic particles contained within the sample 30 can be moved from each of the sample streams 30a,30b, into the buffer fluid 31, in a direction which is towards the channel bed 5d of the main channel 5 (or in a direction which perpendicular to the channel bed 5d of the main channel 5; or perpendicular to a tangent to the apex of the cross section of the main channel if the main channel has a curved channel bed or if the main channel 5 has a v-shaped cross section).
Furthermore, as is shown in
By the time the sample 30 and buffer fluid 31 have reached the second junction 9, all of (or substantially all of) the ferromagnetic, paramagnetic (or super paramagnetic), and/or diamagnetic particles contained within the sample 30 will have been moved out of the sample 30 in both sample streams 30a,30b and into the buffer fluid 31 by the magnetic field.
Due to the arrangement of the sample 30 and buffer fluid 31 within the main channel 5, and since the depth ‘g’ of the two outlet subsidiary channels 8a,8b correspond to the depth of the two inlet subsidiary channels 6a,6b the sample fluid 30, which is now absent of any ferromagnetic (or super paramagnetic), paramagnetic, and/or diamagnetic particles, will flow into the respective outlet subsidiary channels 8a,8b at the second junction 9. More specifically, the first stream 30a of sample fluid 30 is received into the outlet subsidiary channel 8a and the second stream 30b of sample fluid 30 is received into the other outlet subsidiary channel 8a. From the outlet subsidiary channels 8a,8b the sample will flow, via the fourth conduit 14, into the sample drain reservoir 108 where it is collected,
At the second junction 9 the buffer fluid will however contain all the ferromagnetic, paramagnetic (or super paramagnetic), and/or diamagnetic particles which have been removed from the sample 30. Due to the arrangement of the sample 30 and buffer fluid 31 within the main channel 5, and since the depth ‘g’ of the two outlet subsidiary channels 8a,8b is less than the depth of the main channel 5, the buffer fluid containing the ferromagnetic, paramagnetic (or super paramagnetic), and/or diamagnetic particles will remain in the main channel 5 (will not flow into either of the outlet subsidiary channels 8a,8b) and will flow, via the third conduit 13, into the buffer drain reservoir 107.
In the above example, in the main channel 5 the flow rate of the sample 30 flowing along the main channel 5 is equal to the flow rate of the buffer fluid 31 flowing along the main channel 5; the ratio between flow rate of sample 30 in the inlet subsidiary channels 6a,6b and buffer sample 31 in main channel 5 at the first junction 7 is 0.1-10 and is preferably 0.5-2; and the ratio between flow rates of sample in the outlet subsidiary channels 8a,8b and buffer in main channel at the second junction is 0.1-10 and is preferably 0.5-2.
Referring to
The interface component 40 further comprises a plurality of elements 41, each of which can be selectively connected to a pneumatic system which can provide a fluid (such a pressurized air) to the elements 41. In this example the interface component 40 comprises sixteen elements 41, however it will be understood that the interface component 40 may comprise any number of elements 41; preferably the interface component 40 comprises at least four elements 41.
Each element 41 comprises an input port 42 which can be selectively fluidly connected to a pneumatic system; a flow restrictor 43, which is fluidly connected to the input port 42, wherein the flow restrictor 43 is configured to restrict the flow of fluid through the element 41; and an aerosol filter 49 which is arranged to be in fluid communication with the adjustable flow restrictor 43. In this example the aerosol filter 49 is defined by a layer 49 of hydrophobic material; the layer 49 comprising pores having a size 0.22 μm (or at least in the range 0.1-0.3 μm).
The interface component 40 further comprises a platform 46 which supports each of the magnetic assemblies 44 and elements 41. In this example the platform 46 is modular composed of two flat-gaskets 46a,46b and main member 46c; each of the two flat-gaskets 46a,46b are received into a respective cut-out 146 which is defined in the main member 46c.
The interface component 40 further comprises a plurality of outlets 45a-p, each of the outlets 45a-p is in fluid communication with a respective element 41, so that fluid can flow from the element 41, out of the interface component, via the outlets 45a-p. In the example illustrated in
The number of outlets 45a-p should preferably correspond to the number of elements 41; accordingly in this example the interface component 40 comprises sixteen outlets 41. However it will be understood that the interface component 40 may be provided with any number of outlets 4a-p; preferably the interface component 40 comprises at least four outlets 45a-p. Each of the outlets 45a-p can be selectively arranged to be in fluid communication with a respective sample source reservoir 105, buffer source reservoir 106, buffer drain reservoir 107, or sample drain reservoir 108, of the microfluidic device 1.
Referring to
A capillary member 701, which comprises an intermediate channel 715, is interposed between the inlet channel 708 and outlet channel 717. The intermediate channel 715 has dimensions smaller than the dimensions of the inlet and outlet channels 708,717; specifically the diameter of the intermediate channel 715 is less than the diameters of each of inlet and outlet channels 708,717. Preferably the intermediate channel has a circular cross section that has a diameter which is between 1-100 μm. In this example the capillary member 701 is composed of glass; however it will be understood that capillary member 701 may be composed of any suitable material e.g. polymer.
The flow restrictor 43 comprises a male member 703 and female member 704. The male member 703 comprises the inlet member 707, and the female member 704 comprises the outlet member 716.
The male member 703 and female member 704 are configured so that they can mechanically cooperate with each other so that the male and female members can be fixed together. In this example the male member 703 has an external tread 721, and the female has a corresponding internal thread 722, which allow the members 703,704 to be fixed together. The male member 703 further comprises ribbing 711 defined an outer surface thereof, and the female member 704 further comprises ribbing 718 on an outer surface thereof; the ribbings 711,718 facilitate gripping of the members 703,704 as the members 703,704 are rotated with respect to one another so that their respective threads 721,722 can engage one another.
When the male member 703 and female member 704 are mechanically cooperated, an end extremity 703a of the male member 703 will abut the female member 704 at an interface 725.
At its end extremity 703a the male member 703 comprises an annular groove 726 defined by perpendicular surfaces 726a,726b. An o-ring 702 abuts both surfaces 726a,726b. The o-ring also abuts surface 704a which defines a base of the female member 704. The capillary member 701 passes through the o-ring 702; the diameter of the o-ring is substantially equal to the diameter of the capillary member 701 so that the o-ring also abuts an outer surface 701b of the capillary member 701. In the present embodiment the ratio of the cord thickness of the o-ring 702 to the inner diameter ‘r’ of the o-ring is 0.5 (or 0.8 for example); however the ratio of the cord thickness of the o-ring to the inner diameter may be any value between 0.5-1.
In a variation of the embodiment the annular groove 726 may be defined in the female member and the o-ring 702 will be arranged to abut the surfaces which define the annular groove in the female member; for example the surface 704a the surface 704a which defines the base of the female member 704 may comprise an annular groove defined therein, and the o-ring 702 abuts surfaces which define the annular groove.
The male member 703 has a pocket 719a defined therein; and the female member 704 has a pocket 719b defined therein. The pockets 719a,b can each receive a portion of the capillary member 701, so that a portion of length of the capillary member 701 is contained within the pocket 719a of the male member 703, and another a portion of length of the capillary member 701 is contained within pocket 719b of the female member 704.
The depth of the pocket 719a in the male member 703 such that when the capillary member 701 is positioned into the pocket 719a, such that capillary member 701 abuts a base 719c of the pocket 19a, at least 0.5 mm of the length of the capillary member 701 extends out of the pocket 19a of the male member 703. In the example illustrated in
In an further aspect of the present invention, an assembly comprising a interface component 40 and a plurality of capillary members 701 each of which comprises an intermediate channel 715, but the length ‘L’ of the capillary members 701 differ between each of the plurality of capillary members 701 so that the each have intermediate channels 715 of different lengths. In a preferred embodiment the diameter of the intermediate channels 715 of the plurality of capillary members 701 are equal. The plurality of capillary members 701 of different length 12 can be used to achieve different levels of restriction to the flow through an element 41 of the interface component 40. A user can select from the plurality of capillary members 701 a capillary member 701 which has a length which will provide the appropriate resistance to flow; for example in order to increase the restriction to flow through an element 41, the user can replace the capillary member 701 in said element 41 with a capillary member 701 which has a longer length ‘L’; likewise in order to decrease the restriction to flow through an element 41, the user can replace the capillary member 701 in said element 41 with a shorter capillary member 701. Importantly, the depth of the pocket 719a provided in the male member 703 plus the depth of the pocket 719b which is provided in the female member 704 must be equal to, or greater than, the length of the longest capillary member 701 in the plurality of capillary members 701.
Referring to
One end of the plunger 60 is connected to a means for generating a magnetic field 513. In this example means for generating a magnetic field 513 is a permanent magnet 513. It will be understood that any suitable means for generating a magnetic field may be provided.
The plunger 60 comprises a shaft 61 which has a cap member 606 at a first end 61a thereof, and a support member 512 (only one pin shown in
The plunger 60 further comprises an electromagnet 603 which is housed within a housing 603. The plunger 60 comprises a biasing means in the form of a spring 605 which biases the shaft 61 towards a first position; the spring 605 is interposed between the cap member 606 on the shaft 61 and housing 603. The electromagnet 603 cooperates with the shaft 61 such that operating the electromagnet 603 forces the shaft 61 to move, against the biasing force of the spring 605, towards a second position.
The permanent magnet 513 has a shape which corresponds to the shape of the groove 15 in the microfluidic device 1. Specifically permanent magnet 513 has a cross sectional shape which corresponds to the cross sectional shape of the groove 15 in the microfluidic device 1. In the example shown in
It will be understood that the permanent magnet 513 may have any suitable shape. Preferably the shape of permanent magnet 513 will correspond to the shape of the groove 15 defined in the microfluidic device 1 which is to be used with the interface component, so that the permanent magnet 513 can fit snugly into the groove 15 of the microfluidic device 1. In the above-mentioned example permanent magnet 513 had a triangular cross section, thus making it ideally suitable for use with microfluidic devices that have groove 15 which have a v-shaped cross section. It will be understood that the permanent magnet 513 may be configured to have a cross section which has a curved tip (instead of pointed tip in the case of a triangular cross section); interface components with permanent magnet 513 that have curved tip are ideally suited for use with microfluidic devices 1 that have grooves 15 that have a curved cross section; preferably the radius of curvature of the curved tip of the permanent magnet 513 is equal to the radius of curvature of the curved groove 15 in the microfluidic device 1. In an exemplary embodiment the permanent magnet 513 may have a curved tip which has a radius of curvature between 0.05 mm-0.5 mm; and most preferably has a radius of curvature of between 0.2 mm. In another embodiment the permanent magnet 513 may be configured to have cross section which has a flat tip; interface components with permanent magnet 513 that have flat tip are ideally suited for use with microfluidic devices 1 that have grooves 15 with a planar base.
In the assembly 7 shown in
The interface component 40 comprises a row of four magnetic assemblies 44 each identical to the magnetic assembly illustrated in
The elements 41e-h which are also located on the first side 55a of the row of four magnetic assemblies 44 are all also fluidly connected to a pneumatic system 71a which provides positive air flow (indicated by the arrow 50). The positive air flow which is provided to the elements e-h passes through the respective elements 41e-h and into the respective buffer source reservoirs 106 via the respective outlets 45e-h; the positive air flow pushes buffer fluid which is in the respective buffer source reservoirs 106 to flow, via respective first conduits 11, into respective main channels 5 of the microfluidic device 1.
The elements 41i-l which are located on a second, opposite, side 55b of the row of four magnetic assemblies 44 are all fluidly connected to a pneumatic system 71b which provides negative air flow (indicated by the arrow 51). The negative air flow which is provided to the elements 41i-l passes through the respective elements 41i-l and into the respective sample source reservoirs 105 via the respective outlets 45i-l; the positive air flow sucks the buffer fluid, which contains ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles which were removed from the sample, from the main channel 5 into respective buffer drain reservoirs 107, via the third conduit 13.
The elements 41m-p which are also located on the second, opposite, side 55b of the row of four magnetic assemblies 44, are also all fluidly connected to a pneumatic system 71b which provides negative air flow (indicated by the arrow 51). The negative air flow which is provided to the elements 41m-p passes through the respective elements 41m-p and into the respective sample drain reservoirs 108 via the respective outlets 45m-p; the positive air flow sucks the sample fluid, which is absent of ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles, from the main channel 5 into respective pairs of outlet subsidiary channels 8a,8b; along the respective pairs of outlet subsidiary channels 8a,8b; and subsequently into respective sample drain reservoirs 108, via the fourth conduit 14.
The assembly 70 can be used to perform a method according to a further embodiment of the present invention. The assembly 70 is provided. A sample containing ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles, is provided in at least one of the sample source reservoirs 105; in this example the sample is provided in all of the sample source reservoirs 105 in the microfluidic device (in this example microfluidic device 1 comprises four sample source reservoirs 105). A buffer fluid is provided in at least one of the buffer source reservoirs 106; in this example sample is provided in all of the buffer source reservoirs 106 in the microfluidic device (in this example microfluidic device 1 comprises four buffer source reservoirs 106). In this example there are also a corresponding number of buffer drain reservoirs 107 and source drain reservoirs 108 i.e. four buffer drain reservoirs 107, and four source drain reservoirs 108.
Once the respective sample source reservoirs 105 and buffer source reservoirs 106 have been filled, the interface component 40 is then arranged to mechanically cooperate with the microfluidic device 1. Specifically the interface component 40 is arranged so that: the outlets 45a-d overlay a respective sample source reservoir 105 of the microfluidic device 1 so that the outlets 45a-d are in fluid communication with a respective sample source reservoir 105; the outlets 45e-h overlay a respective buffer source reservoir 106 of the microfluidic device 1 so that the outlets 45e-h are in fluid communication with a respective buffer source reservoir 106; the outlets 45i-l overlay a respective buffer drain reservoir 107 of the microfluidic device 1 so that the outlets 45i-l are in fluid communication with a respective buffer drain reservoir 107; the outlets 45m-p overlay a respective sample drain reservoir 108 of the microfluidic device 1 so that the outlets 45i-L are in fluid communication with a respective sample drain reservoir 108.
By arranging the interface component 40 to mechanically cooperate with the microfluidic device 1 in the manner mentioned above, the permanent magnet 513 of each magnetic assembly 44 is aligned over a respective groove 15 of the microfluidic device 1. At this stage the electromagnets 603 of each magnetic assembly 44 may be deactivated so that the shaft 61 occupies its first position thus ensuring that the permanent magnet 513 is at a position which is remote from the microfluidic device 1. However once the interface component 40 has been arranged to mechanically cooperate with the microfluidic device 1 the electromagnet 603 of each magnetic assembly 44 is then operated; the electromagnets force each shaft 61 to move, against the biasing force of the spring 605, to its second position, so that the permanent magnet 513 of each magnetic assembly is moved into a respective groove 15 in the microfluidic device 1. Once received into the groove 15 the permanent magnets 513 is configured to provide a magnetization in the region of a respective main channel 5; the direction of magnetization is perpendicular to the planar channel bed 5d of the main channel, and it also perpendicular to the flow of sample and buffer fluid along the main channel 5. Importantly, if the channel bed of the main channel is curved, then the permanent magnets 513 is configured to provide a magnetization in a direction which is perpendicular to a tangent to the apex of the curve of the channel; likewise or if the cross section of the main channel is v-shaped then the permanent magnets 513 is configured to provide a magnetization in a direction which is perpendicular to a tangent to the apex of the channel. Most preferably the means for generating a magnetic field 513, which in this example is the permanent magnet 513, has a cross section which is tapered in a direction towards the main channel 5. Preferably, the means for generating a magnetic field 513, which in this example is the permanent magnet 513, will be configured to provide a magnetization in a direction which is perpendicular to a longitudinal axis of the permanent magnet 513. Most preferably, the means for generating a magnetic field 513, which in this example is the permanent magnet 513, will be configured to provide a magnetization in a direction which is perpendicular to a longitudinal axis of the permanent magnet 513 and which is perpendicular to the plane of the pallet 3 of the microfluidic device.
The pneumatic systems 71a, 71b are then operated to provide respective a positive air flow and negative air flow. The pneumatic system 71a provides a positive air flow 50 to the elements 41a-h which are located on the first side 55a of the row of magnetic assemblies 44, and the pneumatic system 71b provides a negative air flow 51 to the elements 41i-p which are located on a second, opposite, side 55b of the row of four magnetic assemblies 44. When operated the pneumatic systems 71a, 71b cause the sample to flow out of respective sample source reservoirs 105 via the second conduit 12; along respective pairs of subsidiary inlet channels 6a,6b; along the respective main channels 5 (simultaneously with the buffer fluid) where ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles are removed from the sample; and subsequently along respective pairs of outlet subsidiary channels 8a,8b; and from there into respective sample drain reservoirs 108 via respective fourth conduits 14. When operated the pneumatic systems 71a, 71b cause the buffer fluid to flow out of respective buffer source reservoirs 106 via the first conduit 11; along the main channel 5 (simultaneously with the buffer fluid) where the buffer fluid will receive ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles which have been removed from the sample; and subsequently into respective buffer drain reservoirs 107 via respective third conduits 13.
The sample flowing into the respective main channels from the respective pairs of inlet subsidiary channels 6a,6b will form two streams 30a,30b of sample flowing in each respective main channel 5. Importantly as the depth ‘d’ of each of the pairs of inlet subsidiary channels 6a,6b is less than the depth ‘f’ of the respective main channels 5, along the main channel 5 between respective first and second junctions 7,9, buffer fluid 31 is interposed between each of the sample streams 30a,30b and the channel bed 5d of the main channel; also buffer fluid will be interposed between the two sample streams 30a,30b.
As the sample and buffer fluid simultaneously flow along the respective main channels 5, the magnetization provided in the region of the main channels 5 by the respective permanent magnetics 513 move the ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles, which are contained in the sample, in a direction which is perpendicular to the flow of the sample and buffer fluid in the main channel and is also perpendicular to the channel bed 5d of the main channel, out of the sample and into a buffer fluid. In other words the ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles, which are contained in the sample, are moved into the buffer fluid which is located between the sample and channel bed 5d of the main channel 5.
The ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles may also be moved in a direction which is perpendicular to the flow of the sample and buffer fluid in the main channel and is parallel to the channel bed 5d of the main channel. In other words the ferromagnetic, paramagnetic (including super-paramagnetic), and/or diamagnetic particles, which are contained in the sample, may also moved into the buffer fluid which is interposed between the two sample streams 30a,30b flowing in the main channel 5.
Various modifications and variations to the described embodiments of the invention will be apparent to those skilled in the art without departing from the scope of the invention as defined in the appended claims. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiment.
This application is a continuation of U.S. patent application Ser. No. 15/778,581, filed on May 23, 2018, which is a national phase of PCT/IB2015/059220, filed on Nov. 30, 2015. The entire contents of these applications are hereby incorporated by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 6832787 | Renzi | Dec 2004 | B1 |
| 8163254 | Renzi | Apr 2012 | B1 |
| 20020048536 | Bergh et al. | Apr 2002 | A1 |
| 20030148342 | Gau | Aug 2003 | A1 |
| 20050151371 | Simmons | Jul 2005 | A1 |
| 20140087359 | Njoroge et al. | Mar 2014 | A1 |
| 20140107589 | Amirouche | Apr 2014 | A1 |
| Number | Date | Country |
|---|---|---|
| WO-0163270 | Aug 2001 | WO |
| Entry |
|---|
| International Search Report and Written Opinion for PCT/IB2015/059220 dated Oct. 18, 2016, 8 pages. |
| Number | Date | Country | |
|---|---|---|---|
| 20210106990 A1 | Apr 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15778581 | US | |
| Child | 17111558 | US |
