Microfluidic network device

Abstract

Microfluidic network device (2) configured to supply reagents to a biological tissue sampling device (1), comprising a plurality of microfluidic inlet channels (12) connected to respective sources of said reagents, at least one common outlet channel (22), and a plurality of valves (36) interconnecting an outlet end (14) of each of said plurality of inlet channels to said at least one common outlet channel.

Claims

1. A microfluidic network device comprising: a base portion comprising a plurality of microfluidic inlet channels and at least one common outlet channel, and a plurality of valves interconnecting an outlet end of each of said plurality of inlet channels to said at least one common outlet channel, wherein each valve of the plurality of valves is associated with one of the plurality of inlet channels and comprises a deflectable member displaceable between a valve closed position in which fluid communication between the associated one of the plurality of inlet channels and the at least one common outlet channel is closed, and a valve open position in which fluid communication between the associated one of the plurality of inlet channels and the at least one common outlet channel is open, said at least one common outlet channel comprises ail channel section consisting of a first plurality of sub-sections and a second plurality of sub-sections interconnecting the sub-sections of the first plurality of sub-sections, forming an alternating sequence of sub-sections of the first and second pluralities of sub-sections, wherein each sub-section of the first plurality of sub-sections is configured to cooperate with a single corresponding valve of the plurality of valves, and each sub-section of the first plurality of sub-sections is positioned adjacent respective said outlet end of the associated one of the plurality of inlet channels, wherein the channel section of the at least one common outlet channel extends in a direction transverse to the inlet channels, and wherein the sub-sections of the first plurality of sub-sections extend transversely to the outlet end of each of said plurality of inlet channels, thus forming a “T” shaped arrangement, wherein each valve of the plurality of valves comprises a valve inlet orifice formed at the outlet end of the associated one of the plurality of inlet channels, and a valve outlet orifice forming a portion of the channel section of the at least one common outlet channel, and separated from the valve inlet orifice by a valve separating wall portion, wherein the deflectable member comprises an elastic membrane that overlaps the inlet and outlet orifices, the valve separating wall portion, and optionally also edge surfaces bounding the valve inlet and outlet orifices.

2. The microfluidic network device according to claim 1, wherein the microfluidic network device is configured to be connected to a sampling device arranged downstream of the microfluidic network device and to which reagents, which may include antibodies, imaging buffers, and washing solutions, are supplied.

3. The microfluidic network device according to claim 1, wherein the outlet ends of adjacent inlet channels are offset such that the plurality of outlet ends are not formed along a straight line, whereby the at least one common outlet channel extends along an oscillating path.

4. The microfluidic network device according to claim 1, wherein the deflectable member extends over the valve inlet orifice, valve separating wall portion, and valve outlet orifice such that when the deflectable member is pressed against the valve separating wall portion, fluid communication between the valve inlet orifice and valve outlet orifice of each valve of the plurality of valves is prevented.

5. The microfluidic network device according to claim 1, further comprising a valve body portion comprising actuation chambers that define a deformable portion of the deflectable member that overlaps the valve inlet and outlet orifices and any surface areas around edges of the valve inlet and outlet orifices, the valve body portion providing a separation between adjacent valves of the plurality of valves.

6. The microfluidic network device according to claim 1, further comprising a valve actuation system comprising pneumatic or hydraulic actuation lines connected to actuation chambers positioned above the deflectable members of the plurality of valves.

7. The microfluidic network device according to claim 1, wherein an outermost inlet channel of the plurality of inlet channels is configured to be connected to a supply of a washing solution configured to ensure that during washing, between application of different reagents, the at least one common outlet channel is fully washed from one end to another end to avoid contamination with liquids of a subsequent treatment cycle.

8. The microfluidic network device according to claim 1, wherein the microfluidic network device includes a mixing network comprising two or more mixing channels interconnected by mixing valves to the at least one common outlet channel configured to direct liquid from reagent lines to circulate within the mixing network.

9. The microfluidic network device according to claim 1, wherein at least one of the plurality of inlet channels comprises flow control portions comprising resistive channels.

10. A method of operating a microfluidic network device including a base portion comprising a plurality of microfluidic inlet channels and at least one common outlet channel, and a plurality of valves interconnecting an outlet end of each of said plurality of inlet channels to said at least one common outlet channel, wherein each valve of the plurality of valves is associated with one of the plurality of inlet channels and comprises a deflectable member displaceable between a valve closed position in which fluid communication between the associated one of the plurality of inlet channels and the at least one common outlet channel is closed, and a valve open position in which fluid communication between the associated one of the plurality of inlet channels and the at least one common outlet channel is open, said at least one common outlet channel comprises channel section consisting of a first plurality of sub-sections and a second plurality of sub-sections interconnecting the sub-sections of the first plurality of sub-sections, forming an alternating sequence of sub-sections of the first and second pluralities of sub-sections, wherein each sub-section of the first plurality of sub-sections is configured to cooperate with a single corresponding valve of the plurality of valves and each sub-section of the first plurality of sub-sections is positioned adjacent respective said outlet end of the associated one of the plurality of inlet channels, wherein the channel section of the at least one common outlet channel extends in a direction transverse to the inlet channels, and wherein the sub-sections of the first plurality of sub-sections extend transversely to the outlet end of each of said plurality of inlet channels, thus forming a “T” shaped arrangement, wherein each valve of the plurality of valves comprises a valve inlet orifice formed at the outlet end of the associated one of the plurality of inlet channels, and a valve outlet orifice forming a portion of the channel section of the at least one common outlet channel, and separated from the valve inlet orifice by a valve separating wall portion, wherein the deflectable member comprises an elastic membrane that overlaps the inlet and outlet orifices, the valve separating wall portion, and optionally also edge surfaces bounding the valve inlet and outlet orifices the microfluidic network device further comprising device inlets fluidically connected to inlet ends of the plurality of inlet channels and a device outlet fluidically connected to the at least one common outlet channel, the method comprising: a) priming each of the plurality of inlet channels by injecting respective reagents in each of the plurality of inlet channels, while expulsing liquid via either a purge line or the device outlet by controlling the valves of the plurality of valves interconnecting the plurality of inlet channels to the at least one common outlet channel, b) priming a sampling device connected downstream to said device outlet, by injecting a first reagent through at least one inlet channel of the plurality of inlet channels and out through the device outlet, c) delivering a second reagent configured to react with the sample to the sampling device, d) optionally delivering a washing liquid, and e) optionally repeating steps c and d for different reagents.

11. The method according to claim 10 comprising pre-pressurization of the device inlets and the device outlet of the microfluidic network device, where the device inlets and the device outlet of the microfluidic network are both connected to a pressure source.

12. The method according to claim 11 wherein a pressure on the device inlets is applied for obtaining a predefined flow rate in one of the plurality of inlet channels or in the at least one common outlet channel.

13. The method according to claim 10 further comprising mixing of a third reagent with a fourth reagent in a mixing network of the microfluidic network device.

Description

(1) Further objects and advantageous features of the invention will be apparent from the claims, from the detailed description, and annexed drawings, in which:

(2) FIG. 1 is a schematic simplified view of a microfluidic network device according to an embodiment of the invention;

(3) FIG. 2a is a perspective schematic view of a microfluidic network device according to an embodiment of the invention;

(4) FIGS. 2b and 2c are perspective schematic cross section views, and FIG. 2d is an exploded perspective schematic cross section view, of the microfluidic network device of FIG. 2a;

(5) FIG. 3 is a perspective schematic view of a base portion of a microfluidic network device according to an embodiment of the invention;

(6) FIG. 4a is a schematic plan view of a portion of a microfluidic network device according to an embodiment of the invention and FIG. 4b is a cross section view through line IVb-IVb of FIG. 4a;

(7) FIGS. 5a and 5b are schematic cross-sectional views of a valve of a microfluidic network device according to an embodiment of the invention, FIG. 5a showing the valve closed and FIG. 5b showing the valve open;

(8) FIGS. 6a, 6b and 6c are schematic illustrations of valve inlet and outlet orifices according to different embodiments.

(9) Referring to the figures, a microfluidic network device 2 comprises a body 3 comprising device inlets 10 fluidically connected via fluid channels in the body to one or more device outlets 34. The body 3 may be made of a monolithic structure or may be made from a plurality of parts that are assembled together. In the illustrated embodiment, the body 3 comprises a base portion 4, an inlet body portion 6 and a valve body portion 8. The microfluidic network device further comprises valves 36 positioned on at least some of the fluid channels for regulating the flow of fluids in the channels.

(10) The microfluidic network device 2 may be connected to one or more fluid sources, including reagent sources and optionally one or more sample sources (depending on the application). In an embodiment, the microfluidic network device may be provided with onboard reservoirs 54 that store in the device a supply volume of reagent or sample sufficient for the applications for which the microfluidic network device is intended. Alternatively, or in addition, the inlet body portion 6 of the microfluidic network device may be connected to external fluid supplies. The reservoirs 54 can be prefilled by injecting liquids into the reservoirs from external sources, or can be provided in the form of prefilled cartridges that are loaded into the microfluidic network device such that they fluidically couple with respective fluid channels of the network device. In an embodiment, at least some of the on-board reservoirs use the same pressure source, for instance a pneumatic actuation system, as the one available to actuate the valves and pump the liquid reagents.

(11) The use of the term “reagent” in the present application is intended to cover a variety of liquids or gases that are used in the microfluidic network device for various applications. Reagents may for instance comprise antibodies, imaging probes, washing buffers, chemical reagents, water, saline solutions and other liquids used in the application concerned. Sample liquids are intended to mean liquids that contain samples on which testing is applied, such samples for instance containing biological tissues or other microbiological matter, pollutants, or other substances on which a test on the properties thereof is intended to be carried out by a sampling device disposed downstream of the microfluidic network device.

(12) The microfluidic network device may also be configured and used for mixing liquids in order to prepare reagents and/or sample containing solutions for a subsequent treatment.

(13) The microfluidic network device may also be configured and used for mixing reagents in view of generating a chemical reaction to prepare a resultant liquid.

(14) In an embodiment, the microfluidic network device 2 may be connected to a sampling device 1 to which reagents (antibodies, imaging buffers, washing solutions, etc. . . . ) are supplied.

(15) In an embodiment connected to a sampling device 1 that is arranged downstream of the microfluidic network device, an optional mixing device may be configured to supply only reagents. The sample, for instance a tissue sample, is provided in the sampling device.

(16) Sampling devices of various types are per se known (for instance as described in WO 2013/128322).

(17) Although the sampling device may be a separate device connected by one or more fluid lines to the microfluidic network device, in an embodiment, the sampling device may be integrally provided in a fixed manner assembled to the microfluidic network device or monolithically formed with the microfluidic device.

(18) The inlet body portion 6 of the microfluidic network device 2 comprises a plurality of inlet channels 12 connected to the device inlet or device inlets 10, each inlet channel 12 comprising an inlet end 14 and an outlet end 16 interconnected fluidically by an intermediate channel section 18. In the embodiments illustrated, there are a plurality of inlet channels 12 which for instance may advantageously be arranged in an essentially parallel juxtaposed manner in the base portion 4.

(19) The microfluidic network device further comprises at least one outlet channel 22 that comprises valve sections 24a positioned adjacent to the outlet ends 16 of the inlet channels 12. The outlet ends 16 of adjacent inlet channels 12 may be offset such that the plurality of outlet ends 16 are not formed along a linear line but along a zigzag or wave shaped line, or other oscillating line shapes. In a preferable embodiment with a single outlet channel 22 adjacent the outlet ends 16 of the inlet channels 12, the common outlet channel thus being proximate to the outlet end 16 of the inlet channel also extends along a generally zigzag, wavy or oscillating path. The offset adjacent outlet ends 16 that form an oscillating arrangement when looking at the plurality of outlet ends 16 allows a more compact arrangement, namely a closer distance dl between adjacent inlet channels by providing more space at the outlet end 16 for positioning of a corresponding valve 36. In effect, the outlet ends 16 are connected to valve portions 24a, 24b of the common outlet channel 22 via a valve 36. The common outlet channel 22 thus extends generally in a direction transverse to the inlet channels 12, or at least the outlet end portion of the inlet channels. In the illustrated embodiments, valve portions 24a of the common outlet channel extend transversely to the outlet end portion of the inlet channel in an essentially “T” shaped arrangement.

(20) The valve 36 may comprise a valve inlet orifice 40 formed at the outlet end 16 of the inlet channel, and a valve outlet orifice 42 above, or forming a portion of the common outlet channel 22, and separated from the valve inlet orifice 40 by a valve separating wall portion 44. The deflectable member 38 extends over the valve inlet orifice 40, valve separating wall portion, and valve outlet orifice 42 such that when the deflectable member 38 is pressed against the valve separating wall portion 44, fluid communication between the valve inlet orifice 40 and valve outlet orifice 42 of the valve is prevented (i.e. the valve is in a closed position). It may be noted that the valve outlet orifice 42 of the valve may either be a small orifice extending to the common outlet channel 22, but preferably forms part of the common outlet channel 22. In the latter variant, when liquid flows through the common outlet channel 22, the valve outlet orifice 42 of the valve 36 does not present any dead volume, and liquid in the valve outlet orifice is carried away by liquid flowing in the common outlet channel 22.

(21) In a preferred embodiment, the valve outlet orifice 42 covered by the deflectable member 38 has a smaller surface area projecting onto the deflectable member 38 than the surface area projected by the valve inlet orifice 40 on the deflectable member 38. Preferably, the surface area of the valve inlet orifice 40 projected on the deflectable member 38 is more than two times the projected surface area of the valve outlet orifice 42, preferably more than three times, and more preferably more than five times. This configuration ensures that even if the pressure in the common outlet channel 22 is greater than the pressure in the inlet channel 12, up to a factor corresponding to the ratio of the surface areas of the valve inlet and outlet orifices, a reverse flow from the common outlet channel 22 into the inlet channel 12 is prevented. This in particular forms a safety mechanism against cross contamination between reagents and also prevents backflow of liquid.

(22) In an embodiment, the valve 36 may be formed by a deflectable member 38 with elastic properties that overlaps the inlet and outlet orifices, the valve separating wall portion 44, and optionally also edge surfaces bounding the valve inlet and outlet orifices 40, 42. The valve body portion 8 may be configured to have actuation chambers 48 that define the deformable portion of the deflectable member 38 that overlaps the orifices 40, 42 and any surface areas around the edges of the orifices. The valve body portion 8 pressing against the membrane 38 or the base portion 4 thus also provides a separation between adjacent valves 36.

(23) In an embodiment, the deflectable member 38 may comprise an elastic membrane, for instance in the form or a sheet of elastically deformable material.

(24) In a variant, the deflectable member 38 may comprise a spring mounted valve plate, plunger or ball (not shown), for example comprising a compression spring that pushes the plate, plunger or ball against the edges of the outlet and inlet orifices 40, 42.

(25) It may be noted that the notion of valve inlet orifice 40 and valve outlet orifice 42 may comprise a single continuous orifice as illustrated in FIG. 6a or a plurality of orifices for instance as shown in FIG. 6b. In particular, the valve inlet orifice, in view of its larger surface area, may be provided with a plurality of smaller orifices in order to provide better support for the deflectable member against the orifices, or to control the ratio of projected surface areas between the inlet and outlet.

(26) The valve 36 may be provided with an actuation system that actively controls opening and closing of respective valves 36.

(27) In a variant however, the valves may be passive and act as check-valves that are actuated by increasing the fluid pressure in the inlet channels 12.

(28) In the active variant, the actuation system may control the valves by various means, for instance by electromagnetic, piezoelectric, pneumatic or hydraulic means that act on the deflectable member, for instance to press on the deflectable member to close the valve, or to release pressure on the deflectable member, or to lift up the deflectable member, to open the valve.

(29) In an advantageous embodiment, the actuation system may comprise a pneumatic actuation system whereby a pneumatic actuation line 50 connects to an actuation chamber 48 positioned above the deflectable member 38 overlapping the outlet and inlet orifices 40, 42 and edges thereof.

(30) In an embodiment, the pneumatic interface may be operated to close the valve by having a gas pressure inside the actuation chamber 48 that is greater than atmospheric pressure. In a variant, it is also possible that the deflectable member 38 has a positive elastic pressure against the outlet, inlet and valve separating wall portions and the valve opening is actuated by an under-pressure in the actuation chamber 48.

(31) In an advantageous embodiment, there is a single outlet channel 22 that extends to a position adjacent to each outlet end 16 of a plurality of the inlet channels 12, a valve 36 comprising a deflectable member and actuation chamber being positioned over the valve inlet and outlet orifices such that when fluid flows through the common outlet channel it flows past each of the outlet portions of the valve thus eliminating any dead zones.

(32) In an embodiment, an outermost inlet channel 12a may be connected to a washing solution that ensures that during washing, between application of different reagents, the common outlet channel 22 is fully washed from one end 22a to the other end 22b to avoid contamination with liquids of a subsequent treatment cycle. In such an embodiment, an inlet channel 12a at one end of the microfluidic network device connects to an end 22a of the common outlet channel 22 and the other end 22b of the common outlet channel is connected to an outlet 34 of the microfluidic network device that may either be a waste line, purge line, or a line connected to the sampling device.

(33) The microfluidic network device 22 may therefore optionally comprise an outlet connected to the sampling device 1 as well as one or more purge or waste lines 37 for expulsing liquid without going through the sampling device 1 or other device downstream of the device outlet, or for initial priming of the device during elimination of bubbles within the microfluidic network channels.

(34) In a variant of the invention, the microfluidic network device may be provided with a mixing network 30 comprising two or more mixing channels 32 interconnected by valves 36 that may be used to force liquid to circulate within the mixing network which may be provided with different configurations to mix at least two or more liquids. The liquids may be supplied to the mixing networks from reagent lines 33 of the microfluidic network or by one or more sample lines and may be used to mix either two or more reagents or reagents with one or more sampling liquids.

(35) In advantageous embodiments, the intermediate channel sections 18 joining the inlet end 14 to the outlet end 16 of the inlet channels 12, may be provided with flow control portions 20. Flow control portions 20 may for instance comprise resistive channels that may be formed for instance by a serpentine channel configuration that slow the flow of fluid through the inlet channels. This allows to have a better control of fluid flow, especially in order to dampen pressure fluctuations present at the inlet end 40 of the inlet channels with respect to the outer end 42 where a valve 36 is positioned, or to control liquid flow through the valves. This also ensures that the flow velocity of different reagents flowing through a microfluidic chamber of the sampling device 5 is substantially the same irrespective on the length of the fluidic path from the inlet end of any inlet channel to the microfluidic chamber.

(36) In an embodiment, the flow control portions 20 may be identical for a plurality of inlet channels 12. Alternatively, or in addition, flow control portions 20 may be configured with different flow resistance properties for different inlet channels. The varying flow resistance portions may be provided in order to take into account the properties (for instance viscosity) of the liquids flowing in the respective inlet channels, or to take into account the liquid volume supply requirements of particular reagents for the intended application.

(37) The mixing network 30 may also comprise various per se known mixing systems for instance serpentine channels, resistive heater-type mixers, arrays of pillars, or tree networks which use flow splitting and recombining, and so on, to achieve effective and efficient mixing of liquids.

(38) The mixing network 30 may comprise an inline valve 36b positioned along the common outlet channel 22, between the mixing inlet and outlet channels 32a, 32b of the mixing network such that reagents can be injected into the inlet channel 32a of the mixing network, flow through the mixing network 30 up through the adjacent mixing outlet channel 32b of the mixing network without flowing through the common outlet channel 22. In other words the inline valve 36b along the common outlet channel section 22c between mixing network fluid channels 32a, 32b can be used to force flow of reagents through the mixing network 30. The mixing network can be switched on and off by controlling the valves 36a, 36b, 36c between the inlet and outlet lines 32a, 32b of the mixing network and the common outlet channel 22 of the mixing device.

(39) By way of example referring to FIG. 1, to mix a plurality of reagents, the corresponding reagent valves are opened, sequentially or simultaneously, while the mixer valves 36a, 36c are open and the in-line valve 36b closed. Reagent liquids thus flow into and through the mixer network 30. To bypass the mixer network, the mixer valves 36a, 36c may be closed and the inline valve 36b opened. Circulation of liquid through the mixer network may be unidirectional, or may be reversible to operate a forward and reverse flow of liquid in the mixer network for better mixing.

(40) In an embodiment, both the inlets 12 and one or more outlets 34 of the microfluidic network device may be under a positive pressure, namely a pressure above atmospheric pressure, in order to reduce bubble formation within the microfluidic network device, by having a higher than atmospheric pressure inside the microfluidic environment. Flow between inlet 12 and outlet 34 may thus be controlled by a differential pressure, by increasing the pressure on the inlet side, and/or lowering the pressure on the outlet side.

(41) TABLE-US-00001 List of references used microfluidic network device 2 device inlets 10 device outlet 34 body 3 base portion 4 inlet body portion 6 valve body portion 8 fluid channels inlet channel 12 first inlet channel 12a inlet end 14 outlet end 16 intermediate channel section18 flow control portion 20 (resistive, e.g. serpentine portion) common outlet channel 22 valve sections 24, 24a, 24b intermediate sections 26 first end 22a purge channel 28 mixer network 30 mixing channels 32 mixer valves 36a, 36b, 36c valves 36 (reagent, mixer, purge, exit, ...) deflectable member 38 valve inlet orifice 40 valve outlet orifice 42 valve separating wall portion 44 actuation system actuation chamber 48 actuation line 50 reagent and sample sources onboard reservoir 54 reagent line 33 outlet line 35 purge line 37 sampling device 1