WO2001049412A1

WO2001049412A1 - Flow controlling device and method

Info

Publication number: WO2001049412A1
Application number: PCT/EP2000/013067
Authority: WO
Inventors: Rudolf Rigler; Johan Holm
Original assignee: Acreo Ab
Priority date: 1999-12-30
Filing date: 2000-12-21
Publication date: 2001-07-12
Also published as: SE9904858D0; AU2675601A

Abstract

Device for switching the direction of flow in an intersection between a plurality of microchannels (1, 3, 5) which meet at an intersection (9) wherein at least one of said microchannels (5) is provided with pressure pulse generating means (17, 19) for changing the flow through said microchannels (1, 3, 5).

Description

Flow controlling device and method

Field of the Invention

The present invention relates to devices and methods for controlling the flow of fluids in microchannels.

Prior Art

In the field of micro-assaying, pharmaceutical production and other processes using small particles it is often necessary to supply or extract very small doses or samples of a reagent or substance being tested. In some cases it is even desirable to dispense or separate only one molecule/particle of the substance. In order to achieve this, volumes of liquid containing molecules/particles of substances of interest need to be made to flow through microchannels, i. e. channels have widths and heights which have dimensions in the order of micrometers, and the flow needs to be switched between different outlets so that the molecules/particles of interest are directed to one outlet while the bulk of the rest of the liquid is sent to another outlet. In order to ensure that the molecules/particles of interest are directed to the correct microchannel, the time between the molecule/particle being detected and it being switched should be as short as possible, preferably around I millisecond or less.

One way of switching liquid flow between intersecting microchannels is presented in US patent no. 5 726 404 which describes a device for switching flow between intersecting microchannels by manipulating external driving pressures. In this device a switch comprises three intersecting microchannels, each having a liquid reservoir at its non-intersecting end for liquid inlet and outlet. It has means for applying a driving pressure to each reservoir and means for switching the driving pressure. The switch works by establishing a flow from a first microchannel to a second microchannel by applying a pressure differential between the first and second reservoirs while simultaneously preventing flow into the third microchannel by applying a pressure to the third microchannel which equals the pressure at the junction of the three microchannels. By switching one or more driving pressures, the flow to the second reservoir can be stopped and the liquid flow directed to the third microchannel. A problem with this prior art device is that it needs a driving pressure means for each reservoir and accurate pressure sensing means at the junction of the three microchannels or extensive flow testing and calibrating. Furthermore, it is rather slow acting, as pressure pulses must travel the length of the microchannel from the reservoir to the intersection of the microchannels before the liquid can be made to change direction. Additionally, relatively large pressure pulses are needed in order to overcome the pressure drop in the microchannels. These large pressure pulses require stronger microchannels and lead to larger devices. This is means that such prior art devices are unsuitable for molecule/particle selecting systems when switching times of around 1 millisecond are needed.

Summary of the Invention The present invention relates to a method and device for high speed switching of fluid flow between intersecting microchannels. The fluid flow is controlled by manipulating local pressures near to the intersecting microchannels. The local pressures are manipulated by a local change in a microchannel dimension. In this way, rapid switching can be achieved, as the pressure pulse only has to travel a short distance.

In a preferred embodiment of the invention the local change in the microchannel dimension is achieved by using a piezoactuator. In this way, rapid switching can be achieved, as piezoactuators can have rapid reaction times.

The present invention further includes devices in which the local pressure is manipulated upstream of the intersecting microchannels. This enables switching to be controlled by temporarily interrupting a laminar flow control stream.

The present invention also, includes devices in which the local pressure is manipulated downstream of the intersecting microchannels. This enables switching to be controlled by temporarily reducing the flow through a microchannel.

The present invention will be illustrated below by means of non-limiting examples of embodiments.

Brief Description of the Figures

Figure 1 shows a schematic plan view of a first embodiment of a flow switching device in accordance with the invention in which the flow is directed towards a first outlet; Figure 2 shows the device of fig ire 1 in which the flow is directed towards a second outlet;

Figure 3 shows a cross-section aioπg line 111-10 of figure 2.

Figure 4 shows a schematic plan view of a second embodiment of a flow switching device in accordance with the invention in which the flow is directed towards a first outlet;

Figure 5 shows the device of figure 4 in which the flow is directed towards a second outlet;

Figure 6 shows an example of an external optical detecting system for detecting fluorescence;

Figure 7 shows an example of a particle detecting system using laser scattering; and

Figure 8 shows an example of a particle detecting system using thermal lensing.

Detailed Description of Embodiments Illustrating the Invention

Figures I and 2 show schematically in plan view three intersecting microchannels in a first embodiment of a flow switching device in accordance with the present invention.

Microchannels 1 , 3 and 5 can be formed, for example by etching or embossing or other suitable methods in a micromachining process, in a substrate 7 and covered by a cover plate 8 (see figure 3). Microchannels 1, 3, 5 can have any suitable cross-sectional shape, for example square, rectangular or semi-circular cross-sections, in which the maximum width or diameter is preferably in the range of 0. 1-200 micrometers. Microchannels 1, 3 and 5 meet at an intersection 9. The distal end 11 of microchannel 1, i.e. the end that is furthest away from intersection 9, is connected to a fluid supply (not shown). The distal end 13 of microchannel 3 is connected to a sample-receiving reservoir (not shown). The distal end 15 of microchannel 5 is connected to a fluid-receiving reservoir (not shown) or some other outlet device. The fluid from the fluid supply contains molecules/particles of a sample that it is desired to separate out of the fluid. In the arrangement shown in figures I and 2 the fluid flows from microchannel I to intersection 9 and then along microchannels 3 and 5. The pressure difference between intersection 9 and the proximal ends of microchannels 3, 5 i.e. the ends which are nearest away from the intersection determines the proportion of the fluid from microchannel I which travels down each micro-channel 3, 5. By arranging for the pressure difference (Δp 15) between the distal end 15 of microchannel 5 and intersection 9 to be much greater than the pressure difference (Δp 13) between the distal end 13 of microchannel 3 and intersection 9, it is possible to ensure that most of the fluid flows from microchannel I to microchannel 5 and the flow directions and relative proportions through the microchannels 1, 3, 5 are illustrated by the relative size of the single-headed arrows in the figures. Thus in figure I most of the fluid flowing through intersection 9 from microchannel I is shown flowing out through microchannel 5.

A chamber 17 interrupts microchannel 15. As shown in figure 3, chamber 17 supports pressure pulse generating means 19. Pressure pulse generating means 19 is preferably a piezoactuator 19 which can be controlled by a control device 20 to expand in the direction towards the cavity 17. This expansion reduces the size of chamber 17 and produces an increase of pressure in microchannel 5. This increase of pressure is in the form of a pressure pulse that can be given a precise rise time, a precise duration and a precise fall time by the control means 20. This pressure pulse is adapted to make the pressure difference (Δp 17) between the chamber 17 of microchannel 15 and intersection 9 to be much less than the pressure difference (Δp 13) between the distal end 13 of microchannel 3 and intersection 9. This can be achieved by adapting the rise and fall time of the pressure pulse. Depending on the fluid being used and the shape and dimensions of the microchannels, it can be advantageous to have a pressure pulse which has a rise time which is shorter than the fall time, or vice versa. When the pressure pulse reaches the fluid at intersection 9, most of this fluid is diverted towards microchannel 3. Thus actuation of the piezoactuator 19 temporarily causes most of the fluid to flow from microchannel I to microchannel 3 as shown in figure 2. The temporary flow directions and relative proportions through the microchannels 1, 3, 5 are illustrated by the relative size of the single-headed arrows in the figures. Once the pressure pulse has passed the intersection 9, the flow though intersection 9 and microchannels 3 and 5 returns to its original proportions as shown in figure 1. Figures 4 and 5 show schematically in plan view five intersecting microchannels (V, 3', 5 21, 23) in a second embodiment of a flow switching device in accordance with the present invention. Microchannels V, 3', 5', 21, 23 meet at an intersection 9' with an elongated section 25. The distal end 11' of microchannel 1' is connected to a fluid supply (not shown) that contains molecules/particles of a sample that it is desired to separate out of the fluid. The distal end 13' of microchannel 3 is connected to a sample-receiving reservoir (not shown). The distal end 15' of microchannel 5' is connected to a fluid-receiving reservoir (not shown) or some other outlet device. In arrangement shown in figures 4 and 5 microchannel 21 carries a control flow of fluid which impinges on the fluid flowing from microchannel 1' when it enters the elongated section 25 of intersection 9' and forces all or most of the fluid to flow to microchannel 5'. MicroChannel 23 also carries a control flow of fluid that is normally less than the control flow from microchannel 21 and which therefore is too small to influence the flow of the fluid from microchannel V. MicroChannel 23 is provided with a chamber 17' that supports pressure pulse generating means 19'. Pressure pulse generating means 19' is preferably a piezoactuator 19' that can be controlled by a control device 20' to expand in the direction towards the cavity 17'. This expansion reduces the size of chamber 17' and produces an increase of pressure in microchannel 5'. This increase of pressure is in the form of a pressure pulse that can be given a precise rise time, a precise duration and a precise fall time by the control means 20. This pressure pulse is adapted to temporarily overcome the influence of the control flow from microchannel 21 and to divert the flow from microchannel 1' into microchannel 13' as shown in figure 5. Once the pressure pulse has travelled past the junction of channel 23 with microchannel 1' its effect diminishes and the flow of fluid from microchannel returns to its original path to microchannel 5' as shown in figure 4. Thus actuation of the piezoactuator 19' temporarily causes most of the fluid to flow from microchannel 1' to microchannel 3'. The temporary flow directions and relative proportions through the microchannels V, 3', 5', 21, 23 are illustrated by the relative size of the single- headed arrows in the figures.

The devices in accordance with the invention can be provided with detection devices 27, 27' that detect the presence of molecules/particles of interest in the flow in, or from, microchannel 1, V. The detection devices 27, 27' can produce detection signals that are transmitted to the control device 20, 20', which subsequently actuates pressure pulse generating means 19, 19'. The detection devices can be positioned at any place in the switching device which allows sufficient time to activate the pressure pulse generating means 19, 19' to influence the flow before the molecule/particle of interest has passed the intersection 9, 9'. Suitable detection devices could comprise an external optical detector that detects, through a transparent side or lid of the device, light or other electromagnetic radiation emitted or reflected or refracted by the molecules/particles of interest.

An example of an external optical detecting system is shown in figure 6. Figure 6 shows schematically (and not to scale) a confocal microscope device 61 which detects fluorescence from molecules or particles in a microchannel 63 in a flow switching device 65 in accordance with the present invention. Laser light, shown by solid lines, from a laser source 67 passes through a prefocusing lens 69 and is reflected by a dichroic 71 mirror through a microscope objective 73 which focuses the light into the microchannel 63. The side 75 of the microchannel 63 facing the microscope objective 73 is transparent to laser light and fluorescent light in at least the region that the microscope objective 73 is focused on. The laser light excites the molecules or particles of interest, which then emit fluorescent light of, for example, a wavelength of between 450-700 nm. This fluorescent light, shown by dotted lines, passes through the transparent side 75 of the microchannel 63 and is focused by the microscope objective 73, through the dichroic mirror 73 and bandpass filters 77 which only allow through fluorescent light of the desired frequency, onto a pinhole 79. Behind this pinhole 79 is a photon counting detector 81. This detects the fluorescence emitted by molecules or particles of interest and sends a signal to a control device (not shown) which causes the pressure pulse generating means to be actuated as described above.

Another example of a particle-detecting device is shown in figure 7. Figure 7 shows schematically (and not to scale) a microchannel 81 in which a fluid flows. This fluid flow carries particles 83 of interest, which it is desirable to detect. A laser beam 85 containing light of a known wavelength 11 is focused into the microchannel 81 substantially at the middle of the microchannel. A detector 87 which is preferably adapted to detect just light of the wavelength kl emitted by the laser is positioned on the opposite side of the microchannel 81 in a position such that it's detector inlet 89 cannot detected the focused laser beam when only fluid passes through the region of the microchannel 81 where the laser beam is focused. When a particle 83 passes through the laser beam it scatters the laser light in all directions - as shown by dotted lines. Some of this scattered laser light is scattered into the detector inlet 89 of the detector 87 and detected. The detector can then send a signal to a control device (not shown) which causes the pressure pulse generating means to be actuated as described above. Figure 8 shows a further example of a particle-detecting device. Figure 8 shows schematically (and not to scale) a microchannel 91 in which a fluid flows. This fluid flow carries molecules 93 of interest which it is desirable to detect. A laser beam 95 containing light of a known wavelength 12 is focused into the microchannel 91 substantially at the middle of the microchannel 91. A detector 97 which is preferably adapted to detect light of the wavelength A2 in the laser beam 95 is positioned on the opposite side of the microchannel 9 in a position such that it's detector inlet 99 can detected the focused laser beam 95. A second laser beam 101 emitting light of a wavelength X3 which can be absorbed by the molecules of interest is also focused substantially at the middle of the microchannel 91. If a molecule of interest 93 enters this second laser beam 10 1 then it absorbs the laser light and heats up. This causes a transfer of heat to the fluid surrounding the particle. This changes the refractive index of the fluid. This deflects the laser beam 95 (as shown by the dotted line) and causes the intensity of the light received by the detector 97 to change. This change causes the detector 97 to send a signal to a control device (not shown) which causes the pressure pulse generating means to be actuated as described above.

While the invention has been illustrated with embodiments showing microchannels provided with chambers, it is of course possible to provide the microchannel itself with pressure pulse generating means. This can be achieved by making the microchannel large enough to support a pressure pulse generating means and/or making the pressure pulse generating means as small as, or smaller than, the width of a microchannel.

Claims

1. Device for switching the direction of flow in an intersection between a plurality of microchannels (1, 3, 5; V, 3', 5', 21, 23) which meet at an intersection (9; 9') characterised in that at least one of said microchannels (5; 23) is provided with pressure pulse generating means (19; 19').

2. Device according to claim 1 characterised in that said pressure pulse generating means (19; 19') is a piezoactuator.

3. Device according to any of the previous claims characterised in that said pressure pulse generating means (19; 19') is provided on, or in, a chamber (17; 17') in said microchannel (5; 23).

4. Device according to any of the previous claims characterised in that said pressure pulse generating means (19; 19") is positioned between said intersection (9; 9') and the distal end of said microchannel (5; 23).

5. Device according to any of the previous claims characterised in that it comprises a detecting device (27, 27') for detecting the presence of molecules or particles of interest in the flow.

6. Method for switching the direction of flow in an intersection between a plurality of microchannels (1, 3, 5; 1', 3', 5', 21, 23) which meet at an intersection (9; 9') characterised in the steps of: providing at least one of said microchannels (5; 23) with pressure pulse generating means

(19; 19'); and, providing a control device (20) for actuating said pressure pulse generating means to produce a pressure pulse when the direction of flow is to be switched.

7. Method in accordance with claim 6 characterised in the step of providing a detecting device (27, 27') for detecting the presence of molecules or particles of interest in the flow.