EP2332653A1

EP2332653A1 - Systems and method for manipulating liquid fluids in microfluidic devices

Info

Publication number: EP2332653A1
Application number: EP09179110A
Authority: EP
Inventors: Stephan Korner; Edwin Oosterbroek; Rainer Jaeggi; Vuk Siljegovic
Original assignee: F Hoffmann La Roche AG; Roche Diagnostics GmbH
Current assignee: F Hoffmann La Roche AG; Roche Diagnostics GmbH
Priority date: 2009-12-14
Filing date: 2009-12-14
Publication date: 2011-06-15

Abstract

The present invention pertains to various systems for manipulating liquid fluids. A first system includes a microfluidic device (102) provided with at least one microfluidic structure communicating with at least one port (104) for introducing said liquid fluid into said microfluidic structure, and at least one nozzle (108) adapted for ejecting an air stream (109), said nozzle being operatively coupled to said port so that said ejected air stream is either made to flow across said port to generate said negative pressure in said microfluidic structure or is made to at least partially flow into said port to generate said positive pressure therein. Alternatively, a substrate may face the device which can be spun around a spin axis and is being provided with one or more step-like protrusions for generating a positive and/or negative pressure. Yet alternatively, a support for supporting the device which can be spun around a spin axis can be envisaged. The support is being provided with at least one duct for generating a positive and/or negative pressure in the microfluidic structure. Yet alternatively, an open-top chamber adapted to be covered by the microfluidic device including at least one cavity communicating with the port and being connected to a pump can be envisaged. The invention further pertains to a method for manipulating liquid fluids in a microfluidic structure, comprising the following steps of: introducing said liquid fluid through one first port into said structure; making air to either flow across said first port or a second port being different from the first port and communicating with the microfluidic structure to generate a negative pressure in said structure and/or to at least partially flow into said port to generate a positive pressure in said structure; and spinning said microfluidic structure around a spin axis to generate a centrifugal force acting on said liquid fluid contained in said microfluidic structure.

Description

TECHNICAL FIELD

The present invention is in the field of medical diagnostics and concerns various systems and a method for the automated manipulation of liquid fluids.

BACKGROUND OF THE INVENTION

In medical diagnostics, a strong demand for the automated analysis of body fluids can be observed which is primarily due to the fact that there is an ongoing increase in the number of clinical analyses. Due to low sample consumption, fast analysis times and high sample throughput, in recent years, many efforts have been made to develop new microfluidic devices, among these centrifugal force based microfluidic devices, for the automated processing of liquid fluids having minute volumes as low as micro-litres. In the technique of using centrifugal force to drive fluids, e.g., disk-like devices ("chips") are spun around a spin axis to transport fluids to a radial-outer position relative to the spin axis. Centrifugal force-based microfluidic devices as such are well-known to those of skill in the art and have been extensively described in the patent literature, e.g., in US patent application publications US 2008/0252905 A1 , US 2008/02371151 A1 and US 2008/0206110 A1 .
In medical diagnostics, it is often desirable that fluids be quickly divided into predetermined volumes for analysis in a variety of assays or tests. Otherwise, in the case of biological fluids, typically a need arises to separate cellular components from the remaining fluid fraction prior to testing. For example, blood analysis typically requires that cellular components be sedimented by centrifugation, followed by manual or automated pipetting of the supernatant blood plasma into separate wells. In the case of using centrifugal force based microfluidic devices, it is known to separate blood plasma from the remaining cellular fraction by use of capillary flow as, e.g., described in US patent 5,242,606 .
In light of the foregoing, it is an object of the invention to provide an improved microfluidic device enabling an easy-to-perform and quick manipulation of liquid fluids according to the specific demands of the user. This object is met by various systems and a method according to the independent claims. Preferred embodiments of the invention are given by the features of the dependent claims.

SUMMARY OF THE INVENTION

As used herein, the term "microfluidic" refers to cross-sectional dimensions which typically are on the order of millimetre and sub-millimetre scale. Cross-sectional dimensions may, e.g., range from 0.01 millimetres to 2 millimetres. Cross-sectional areas may, e.g., range from 0.1 x 0.1 mm² to 2 x 2 mm². Specifically, microfluidic features enable manipulation of fluid volumes which, e.g., are on the order of 100 µl or less at a flow rate, e.g., on the order of 100 µl/sec or slower.
According to the invention, a new system for the automated manipulation of liquid fluids is proposed. Although the system of the invention is particularly suitable for manipulating biological fluids such as body fluids like blood, serum, urine, milk, saliva, cerebrospinal fluid etc., it will be useful with a wide variety of other non-biological fluids which require the transport of portions and/or fractions thereof prior to performing an analysis or assay.
The system of the invention comprises a microfluidic device which is being provided with one or more microfluidic structures for receiving the liquid fluid. Each of the microfluidic structures communicates with at least one port for introducing the liquid fluid into the microfluidic structure.
The system further includes at least one nozzle fluidically connected to a means for supplying flowing-air such as a fan for ejecting an air stream. The nozzle is being operatively coupled to the at least one port in a manner that the ejected air stream is either made to flow across the port to generate a negative pressure in the microfluidic structure by the Venturi effect (Bernoulli principle) or is made to at least partially flow into the port to generate a positive pressure in the microfluidic structure. Specifically, in order to generate a negative pressure in the microfluidic structure using the Venturi effect, air is sucked out of the microfluidic structure via the port. Otherwise, to generate a positive pressure in the microfluidic structure, at least a portion of the pressurized air ejected by the nozzle is made to flow into the microfluidic structure.
In some embodiments, the microfluidic structure communicates with one port. In some other embodiments, the microfluidic structure communicates with plural ports. In some embodiments, the microfluidic structure also communicates with at least one vent for transferring gaseous liquid such as air into/out of the microfluidic structure. In some embodiments, in case of providing plural microfluidic structures, each microfluidic structure communicates with at least one individual port not communicating with any other microfluidic structure. In some other embodiments, in case of providing plural microfluidic structures, more than one microfluidic structure communicate with at least one common port so that the port communicates with plural microfluidic structures.
In some embodiments, the microfluidic structure communicates with at least one first and at least one second port. The first or second ports may be used for introducing liquid fluid into the microfluidic structure. The first or second ports may also be used for generating a positive and/or negative pressure in the microfluidic structure. In some embodiments, the at least one first port is being used for introducing liquid fluid into the microfluidic structure, while the at least one second port is being used for generating a positive and/or negative pressure in the microfluidic structure. Specifically, in the latter case, the at least one second port can also be used for introducing liquid fluid into the microfluidic structure.
As used herein, the term "positive pressure" relates to pressures higher than atmospheric (ambient) pressure and the term "negative pressure" relates to pressures smaller than atmospheric pressure.
The system according to the invention advantageously allows for an easy and quick transport of liquid fluid within the microfluidic structure by a non-contact (contact-less) generation of a positive and/or negative pressure using an air stream ejected by the nozzle.
In some embodiments, the nozzle is operatively coupled to an air guiding face adapted to either guide air ejected by the nozzle across (over) the at least one port or to guide at least a portion of it into the port. In some embodiments, the air guiding face is fixed to the microfluidic device. In that case, e.g., a sealing member can be provided in-between the device and the air guiding face. In some embodiments, the air guiding face is fixed to the nozzle. Specifically, in the former case, the air guiding face and the nozzle can be made of one piece. In some embodiments, the air guiding face is fixed to a component of the system other than the microfluidic device or the nozzle.
In some embodiments, the system includes a spinning device such as a centrifuge for spinning the microfluidic device around a spin axis to generate centrifugal force acting on the liquid fluid as the device rotates. The microfluidic device may, e.g., be embodied as disk provided with plural microfluidic structures which are circumferentially arranged with respect to each other. In some embodiments, the nozzle is arranged in a manner that air can be ejected in a direction against a rotational movement of the microfluidic device so that there is an increased relative movement between the at least one port and air ejected from the nozzle.
According to the invention, another new system for the automated manipulation of liquid fluids is proposed. The system includes a microfluidic device provided with at least one microfluidic structure communicating with at least one port for introducing the liquid fluid into the microfluidic structure. In some embodiments, the microfluidic structure communicates with one port. In some other embodiments, the microfluidic structure communicates with plural ports. In some embodiments, the microfluidic structure also communicates with at least one vent for transferring gaseous liquid such as air into/out of the microfluidic structure. In some embodiments, in case of providing plural microfluidic structures, each microfluidic structure communicates with at least one individual port not communicating with any other microfluidic structure. In some other embodiments, in case of providing plural microfluidic structures, more than one microfluidic structures communicate with at least one common port so that the port communicates with plural microfluidic structures.
In some embodiments, the microfluidic structure communicates with at least one first and at least one second port. The first or second ports may be used for introducing liquid fluid into the microfluidic structure. The first or second ports may also be used for generating a positive and/or negative pressure in the microfluidic structure. In some embodiments, the at least one first port is being used for introducing liquid fluid into the microfluidic structure, while the at least one second port is being used for generating a positive and/or negative pressure in the microfluidic structure. Specifically, in the latter case, the at least one second port can also be used for introducing liquid fluid into the microfluidic structure.
The system further includes a substrate arranged in a manner to face the microfluidic device.
The system yet further includes a spinning device such as a centrifuge for spinning the substrate and/or the microfluidic device around an, e.g., common spin axis so that the microfluidic device can be rotated relative to the substrate and/or the substrate can be rotated relative to the microfluidic device. In some embodiments, only the microfluidic device can be spun around the spin axis. In some embodiments, only the substrate can be spun around the spin axis. In some embodiments, both the microfluidic device and the substrate can be spun around the spin axis, in which case, it can be preferred to obtain a combined effect in spinning the substrate in the one rotational direction while spinning the microfluidic device in the opposite rotational direction.
In the system, the substrate and/or the microfluidic device are being provided with one or more step-like protrusions protruding towards the respective facing member, i.e., protrusions on the microfluidic device project towards the substrate while protrusions on the substrate project towards the microfluidic device. The protrusions are being adapted to generate a positive and/or negative pressure in an intermediate zone in-between the substrate and the device as the substrate and/or the microfluidic device are being rotated around the spin axis.
In the system, the at least one port communicates with the intermediate zone so as to generate a positive and/or negative pressure in the microfluidic structure depending on the pressure prevailing in the intermediate zone.
According to the invention, another new system for the automated manipulation of liquid fluids is proposed. The system includes a microfluidic device provided with at least one microfluidic structure communicating with at least one port for introducing the liquid fluid into the structure. In some embodiments, the microfluidic structure communicates with one port. In some other embodiments, the microfluidic structure communicates with plural ports. In some embodiments, the microfluidic structure also communicates with at least one vent for transferring gaseous liquid such as air into/out of the microfluidic structure. In some embodiments, in case of providing plural microfluidic structures, each microfluidic structure communicates with at least one individual port not communicating with any other microfluidic structure. In some other embodiments, in case of providing plural microfluidic structures, more than one microfluidic structure communicate with at least one common port so that the port communicates with plural microfluidic structures.
In some embodiments, the microfluidic structure communicates with at least one first and at least one second port. The first or second ports may be used for introducing liquid fluid into the microfluidic structure. The first or second ports may also be used for generating a positive and/or negative pressure in the microfluidic structure. In some embodiments, the at least one first port is being used for introducing liquid fluid into the microfluidic structure, while the at least one second port is being used for generating a positive and/or negative pressure in the microfluidic structure. Specifically, in the latter case, the at least one second port can also be used for introducing liquid fluid into the microfluidic structure.
The system further includes a support for supporting the microfluidic device. The system yet further includes a spinning device such as a centrifuge for spinning the support around a spin axis to generate centrifugal force acting on the liquid fluid contained in the microfluidic structure.
Specifically, in the system of the invention, the support is being provided with at least one duct communicating with the at least one port. The duct is being connected to a pump so that gaseous and/or liquid fluid can be transferred to/out of the microfluidic structure and/or that cooling and/or heating fluid can be circulated within the support for transferring heat (thermic energy) to/from the liquid fluid contained in the microfluidic structure. Hence, the pump can, e.g., be embodied as a gaseous and/or liquid fluid pump adapted for pumping gaseous and/or liquid fluids. In some embodiments, the pump is being used to generate a positive and/or negative pressure in the microfluidic structure, e.g., by introducing and/or withdrawing gaseous liquid such as air into/out of the microfluidic structure. In some embodiments, the pump is being used to introduce and/or withdraw liquid fluid into/out of the microfluidic structure. Specifically, liquid fluid can be introduced into or withdrawn from the microfluidic structure in a dosed manner, e.g., while rotating the microfluidic device regardless the rotational speed of the support. In some embodiments, the pump is being used to circulate gaseous and/or liquid heating and/or cooling fluid within the support in order to heat and/or cool liquid fluid contained in the microfluidic structure. In the latter case, it can be preferable to place a thermal intermediate member (thermal interface) having good thermal conductivity in-between the support and the microfluidic device in order to obtain an improved heat transfer between the duct and the microfluidic structure via the intermediate member. The intermediate member can, e.g., be made of metallic material. Those of skill in the art will appreciate that any other material having sufficient thermal conductivity to comply with the specific demands of the user could be useful for use. In some embodiments, the support for supporting the microfluidic device is being provided with one duct communicating with at least one port and being connected to one pump. In some embodiments, the support for supporting the microfluidic device is being provided with plural ducts communicating with plural ports of one or more microfluidic structures and being connected to one or more pumps Specifically, in case of using plural pumps connected to one or more microfluidic structures, various positive and/or negative pressures can be generated in the one or more microfluidic structures and/or various amounts of gaseous and/or liquid fluid can be transferred to/from the one or more microfluidic structures according to the specific demands of the user. More specifically, plural pumps can be connected to plural ports of one microfluidic structure via plural ducts. Otherwise, plural pumps can be connected to at least one port of plural microfluidic structures via plural ducts.
In some embodiments, the one or more ducts are in fluid communication with a rotary coupling connected to one or more pumps which allows for an easy-to-perform fluidic connection between ducts and pumps. As used herein, the term "rotary coupling" denotes a coupling enabling rotational decoupling between the support and the one or more pumps, so that the support can be rotated relative to the one or more pumps. The rotary coupling is well-known to the skilled persons so that it is not further elucidated herein.
In some embodiments, the system further includes a heating and/or cooling device such as a Peltier device which can produce or absorb heat according to the specific direction of the applied current. The heating and/or cooling device is being arranged in-between the support and the microfluidic device for heating and/or cooling the liquid fluid contained in the microfluidic structure.
According to the invention, another new system for the automated manipulation of liquid fluids is proposed. The system includes a microfluidic device provided with at least one microfluidic structure communicating with at least one port. In some embodiments, the microfluidic structure communicates with one port. In some other embodiments, the microfluidic structure communicates with plural ports. In some embodiments, the microfluidic structure further communicates with at least one vent for transferring gaseous liquid such as air into/out of the microfluidic structure. In some embodiments, in case of providing plural microfluidic structures, each microfluidic structure communicates with at least one individual port not communicating with any other microfluidic structure. In some other embodiments, in case of providing plural microfluidic structures, more than one microfluidic structures communicate with at least one common port so that the port communicates with plural microfluidic structures.
In some embodiments, the microfluidic structure communicates with at least one first and at least one second port. The first or second ports may be used for introducing liquid fluid into the microfluidic structure. The first or second ports may also be used for generating a positive and/or negative pressure in the microfluidic structure. In some embodiments, the at least one first port is being used for introducing liquid fluid into the microfluidic structure, while the at least one second port is being used for generating a positive and/or negative pressure in the microfluidic structure. Specifically, in the latter case, the at least one second port can also be used for introducing liquid fluid into the microfluidic structure.
The system further includes a spinning device for spinning the microfluidic device around a spin axis and an open-top (non-rotated) pressure chamber adapted to be (fully) covered by the microfluidic device. The pressure chamber and the device are being rotationally decoupled, i.e., the microfluidic device can be rotated relative to the pressure chamber. Furthermore, the pressure chamber includes one or more cavities communicating with the one or more ports and being connected to one or more pumps for transferring gaseous and/or liquid fluid from and/or to the microfluidic structure. The pump can be embodied as a gaseous and/or liquid fluid pump adapted for pumping gaseous and/or liquid fluids. In some embodiments, the pump is being used to generate a positive and/or negative pressure in the microfluidic structure, e.g., by introducing or withdrawing gaseous liquid such as air into/from the microfluidic structure. In some embodiments, the pump is being used to introduce and/or withdraw liquid fluid into the microfluidic structure in a dosed manner, e.g., while rotating the microfluidic device. Accordingly, the pump can be used as dosing member for introducing liquid fluids into the microfluidic structure regardless the rotational speed of the microfluidic device.
In some embodiments, the chamber is provided with one cavity communicating with the at least one port and being connected to one pump for transferring gaseous and/or liquid fluid from and/or to the microfluidic structure. In some other embodiments, the chamber is being provided with plural cavities communicating with plural ports of the one or more microfluidic structures and being connected to one or more pumps for transferring gaseous and/or liquid fluid from and/or to the microfluidic structure(s). Specifically, using plural pumps connected to one or more microfluidic structures, various positive and/or negative pressures can be generated in the one or more microfluidic structures and/or various amounts of gaseous and/or liquid fluid can be introduced into and/or withdrawn from the one or more microfluidic structures according to the specific demands of the user. In some embodiments, one cavity of the chamber is being connected to one or more pumps. In some embodiments, plural cavities of the chamber are being connected to one or more pumps. Specifically, the pressure chamber can be provided with plural cavities, each of which communicating with one or more of the ports and being connected to an individual pump, e.g., for generating a positive or negative pressure therein. Accordingly, a variety of pressures can be generated in the microfluidic structure(s) according to the specific demands of the user.
In some embodiments, the system further includes at least one sealing member arranged in-between the open-top pressure chamber and the microfluidic device for air-tightly sealing the pressure chamber covered by the microfluidic device.
In some embodiments of the various above-described systems according to the invention, the microfluidic device is being provided with a recess for receiving a means such as a fleece pad to introduce liquid fluid into the microfluidic structure.
In some embodiments of the various above-described systems according to the invention, the microfluidic structure includes at least two portions, i.e., a first portion and a second portion, both of which having a radial-inner position compared to a reference point given by a radial outermost portion of the microfluidic structure relative to the spin axis. The radial outermost portion of the microfluidic structure is sandwiched in-between the first and second portions, the first and second portions being adjacent thereto. Hence, liquid fluid contained in the microfluidic structure can, e.g., be transported to a radial-inner position against the effect of the centrifugal force by generating a positive and/or negative pressure in the microfluidic structure.
In some embodiments of the various above-described systems of the invention, the microfluidic structure includes plural second ports for generating a positive and/or negative pressure in the microfluidic structure communicating with one first port for introducing liquid fluid into the microfluidic structure, wherein the plural second ports are in parallel relationship with respect to each other. In the latter case, the plural second ports can also be used for transferring liquid fluid into/out of the microfluidic structure.
In some other embodiments of the various above-described systems according to the invention, the microfluidic structure includes plural second ports for generating a positive and/or negative pressure in the microfluidic structure communicating with one first port for introducing liquid fluid into the microfluidic structure, wherein the plural second ports are in serial relationship with respect to each other.
According to the invention, a new method for the automated manipulation of liquid fluids in a microfluidic structure is proposed. The method includes the following steps:
A step of introducing the liquid fluid through one first port into the microfluidic structure.
A step of making air to either flow across the first port or a second port being different from the first port and communicating with the microfluidic structure to generate a negative pressure in the microfluidic structure by the Venturi effect or to make it at least partially flow into the port to generate a positive pressure in the microfluidic structure.
In some embodiments, the method comprises a step of spinning the microfluidic structure around the spin axis to generate a centrifugal force so as to transport the liquid fluid in a first direction having at least a directional component along the centrifugal force. A further step of generating a positive and/or negative pressure in the microfluidic structure, the pressure acting on the liquid fluid in a manner to transport the liquid fluid in a second direction being different from the first direction and having at least a directional component against the centrifugal force. Accordingly, the pressure can be used for transporting the liquid fluid in a radial-inner position compared to a radial-outer position taken by effect of the centrifugal force.
In some embodiments, the method comprises a step of spinning the microfluidic structure around the spin axis to generate a centrifugal force so as to transport the liquid fluid in a first direction having at least a directional component along the centrifugal force. A further step of generating a positive and/or negative pressure in the microfluidic structure, the pressure acting on the liquid fluid in a manner to transport the liquid fluid in the microfluidic structure in a second direction, the second direction being identical or different to the first direction and having at least a directional component along the centrifugal force. Accordingly, the pressure can be used for transporting the liquid fluid in a more radial-outer position compared to a radial-outer position already taken by effect of the centrifugal force. The pressure can in particular be used for the controlled penetration of a liquid fluid barrier such as a geometric valve.
In some embodiments, the microfluidic structure is spun in a direction against the air flowing across or into the port so as to increase a relative velocity between the flowing air and the port.
In some embodiments, the method includes a step of spinning the microfluidic structure to generate centrifugal force so as to transport the liquid fluid from a first radial-inner position to a radial-outer position and a step of generating a positive and/or negative pressure so as to transport the liquid fluid from the radial-outer position to a second radial-inner position relative to the spin axis. The first radial-inner position can be equal to or different from the second radial-inner position.
In some embodiments, the method includes a step of transporting the liquid fluid back and forth in the microfluidic structure while spinning the microfluidic structure. Particularly, either a positive and/or negative pressure is generated in a manner that a force is created sufficient for outbalancing the centrifugal force acting on the liquid fluid so that the liquid fluid is transported to a radial-inner position or is reduced or abruptly stopped so that the centrifugal force transports the liquid fluid to a radial-outer position providing the option of having extra-high acceleration or velocity, if desired, significantly rising Reynold's numbers of the liquid fluid in microfluidic structure. Accordingly, such step can be used for mixing the liquid fluid in the microfluidic structure which can be multiply repeated according to the specific demands of the user. In that, due to high centripetal forces during high rotational speeds, the liquid fluid gets subject to tremendously high accelerations which are bigger than can be achieved by simply starting rotation of the microfluidic structure. The extra-high accelerations and therefore also velocities of the liquid fluid inside the microfluidic structure can significantly rise the Reynold's number so as to achieve more efficient mixing.
In some embodiments, the method comprises a step of maintaining generation of the positive and/or negative pressure for a predetermined time interval to make air bubbles flow through the liquid fluid. Such step can be used for mixing the liquid fluid in the microfluidic structure by air bubbles passing through the liquid fluid.
In some embodiments, while spinning the microfluidic structure, the method comprises a step of maintaining generation of the positive and/or negative pressure for a predetermined time interval, e.g., after transporting the liquid fluid to a radial-inner position so as to cool the liquid fluid by evaporating fluid in a controlled manner and/or to phase-change the liquid fluid from one aggregate condition to another in a controlled manner.

BRIEF DESCRIPTION OF THE DRAWINGS

Other and further objects, features and advantages of the invention will appear more fully from the following description. The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate preferred embodiments of the invention, and together with the general description given above and the detailed description given below, serve to explain the principles of the invention.

FIGS. 1A-1B: are schematic top and sectional views illus- trating an exemplary embodiment of the system according to the invention;
FIGS. 2A-2B: are schematic top and sectional views illus- trating another exemplary embodiment of the system of the invention;
FIGS. 3A-3B: are schematic top and sectional views illus- trating another exemplary embodiment of the system of the invention;
FIGS. 4A-4B: are schematic top and sectional views illus- trating another exemplary embodiment of the system of the invention;
FIGS. 5A-5B: are schematic views illustrating another ex- emplary embodiment of the system of the in- vention;
FIGS. 6A-6B: are schematic perspective and sectional views illustrating another exemplary embodiment of the system of the invention;
FIGS. 7A-7C: are schematic sectional and bottom views il- lustrating another exemplary embodiment of the system of the invention;
FIG. 8: is a schematic sectional view illustrating another exemplary embodiment of the system of the invention;
FIGS. 9A-9B: are schematic perspective and sectional views illustrating another exemplary embodiment of the system of the invention;
FIGS. 10A-10E: are schematic sectional views illustrating variants of the system of FIGS. 9A-9B;
FIG.11: is a schematic sectional view illustrating another exemplary embodiment of the system of the invention;
FIGS. 12A-12B: are schematic sectional views illustrating another exemplary embodiment of the system of the invention;
FIGS. 13A-13B: are schematic sectional views illustrating a method of activating pressure-driven fluid transport in the system of the invention;
FIGS. 14A-14C: are schematic top views illustrating a method of mixing liquid fluids;
FIG. 15: is a schematic top view illustrating another method of mixing liquid fluids;
FIG. 16: is a schematic top view illustrating a method of making liquid fluids flowing through a cuvette;
FIG. 17: is a schematic top view illustrating a method of cooling liquid fluids.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be described in detail below with reference to the accompanying drawings. An exemplary system for manipulating liquid fluids according to the invention is illustrated generally at 101 in FIGS. 1A and 1B.
Accordingly, the system 101 includes a microfluidic device 102 provided with one or more microfluidic structures 103, one of which is shown for the purpose of illustration only. It, however, is to be understood that more than one microfluidic structure 103 can be envisaged according to the specific demands of the user. The microfluidic structure 103 comprises a flow channel 105 for receiving and transporting liquid fluids which communicates with a port 104 opening the microfluidic structure 103 to the atmosphere at an upper face 112 of the microfluidic device 102. The port 104 can be used for generating a positive and/or negative pressure in the microfluidic structure 103.
While not shown in the figures, the microfluidic structure 103 can include another port in fluid communication with the flow channel 105 for introducing any liquid or gaseous fluid of interest into the microfluidic structure 103. Alternatively, the port 104 could also be used for introducing the liquid fluid into the microfluidic structure 103. Furthermore, in particular in the latter case, the microfluidic structure 103 can include a vent for transferring gaseous liquid such as air into/out of the microfluidic structure 103.
The system 101 further comprises a nozzle 108 connected to a means for supplying flowing air such as a fan 106 by an air duct 107. The fan 106 can generate flowing air which is ejected by the air nozzle 108 in an ejected air stream 109.
The system 101 yet further comprises a curved air guiding face 110 fixed to the upper face 112 of the microfluidic device 102 adjacent the port 104. While not shown in the figures, the air guiding face 110 could also be fixed to the nozzle 108, or could be fixed to a system component other than the microfluidic device 102 and the nozzle 108. The curved air guiding face 110 is operatively coupled to the nozzle 108 to guide the ejected air stream 109 in a manner that air flows across the port 104. As a result, a negative pressure can be generated in the microfluidic structure 103 by means of the Venturi effect (Bernoulli's principle). Stated more particularly, the ejected air stream 109 generates a local depression zone adjacent the port 104 so that air contained in the microfluidic structure 103 is aspirated to the ambient via the port 104 as illustrated by an arrow 111. Accordingly, liquid fluid contained in the microfluidic structure 103 can be sucked towards the port 104.
In the system 101, in case of providing plural microfluidic structures 103, each microfluidic structure 103 may, e.g., communicate with one port 104 not communicating with any other microfluidic structure 103. Otherwise, in case of providing plural microfluidic structures 103, more than one microfluidic structures 103 may communicate with at least one common port 104 so that the port 104 communicates with plural microfluidic structures 103.
Referring to FIG. 2A depicting a schematic top view and FIG. 2B depicting a schematic sectional view, another exemplary embodiment of the system 101 for manipulating liquid fluids according to the invention is explained. In order to avoid unnecessary repetitions, only differences with respect to the embodiment of FIGS. 1A and 1B are explained and, otherwise, reference is made to explanations given in conjunction therewith.
Accordingly, in the system 101, the curved air guiding face 110 is operatively coupled to the air nozzle 108 to guide the ejected air stream 109 in a manner that it is at least partially directed into the port 104 to generate a positive pressure in the microfluidic structure 103 as indicated by the arrow 111. Accordingly, liquid fluid contained in the microfluidic structure 103 can be pushed away from the port 104.
With particular reference to FIG. 3A depicting a schematic top view and FIG. 3B depicting a schematic sectional view, another exemplary embodiment of the system 101 for manipulating liquid fluids according to the invention is explained. In order to avoid unnecessary repetitions, only differences with respect to the embodiment of FIGS. 1A and 1B are explained and, otherwise, reference is made to explanations given in conjunction therewith.
Accordingly, the system 101 includes an e.g. disk-like microfluidic device 102 which can be spun around a central spin axis 113, e.g., in clockwise rotational direction as indicated by an arrow 114, e.g., by use of an electric motor or a centrifuge (not shown). The microfluidic device 102 is provided with plural microfluidic structures 103 as explained in connection with FIGS. 1A and 1B which are circumferentially arranged with respect to each other. In correspondence to the plurality of microfluidic structures 103, plural curved air guiding faces 110 are fixed to the upper face 112 of the microfluidic device 102. Specifically, the air guiding faces 110 are operatively coupled to one air nozzle 108 to guide the ejected air stream 109 in such a manner that it flows across the ports 104. As the microfluidic device 102 is spun against the direction of the ejected air stream 109, a combined effect of generating a negative pressure in the microfluidic structures 103 by means of the Venturi effect can be obtained.
With particular reference to FIG. 4A depicting a schematic top view and FIG. 4B depicting a schematic sectional view, another exemplary embodiment of the system 101 for manipulating liquid fluids according to the first aspect of the invention is explained. In order to avoid unnecessary repetitions, only differences with respect to the embodiment of FIGS. 3A and 3B are explained and, otherwise, reference is made to explanations given in conjunction therewith.
Accordingly, the air guiding faces 110 are operatively coupled to one air nozzle 108 to guide the ejected air stream 109 in a manner that it at least partially flows into the ports 104. As the microfluidic device 102 is spun against the direction of the ejected air stream 109, a combined effect of generating a positive pressure in the microfluidic structures 103 can be obtained.
Another exemplary embodiment of the system according to the invention is illustrated generally at 201 in FIG. 5A depicting a sectional side view and 5B depicting a schematic view of the generated pressure distribution.
With particular reference to FIG. 5A, the system 201 includes an e.g. disk-like microfluidic device 202 provided with plural microfluidic structures 203 circumferentially arranged with respect to each other similar to the microfluidic device 102 of FIGS. 3A-3B and 4A-4B. In order to avoid unnecessary repetitions, reference is made to explanations given in conjunction therewith. Contrary thereto, each of the ports 204 opens at a lower face 205 of the microfluidic device 202.
The system 201 further comprises an e.g. disk-like substrate 206 which can be spun around the spin axis 207, e.g., by an electric motor or a centrifuge (not shown). Additionally or alternatively, the microfluidic device 202 can also be rotated against the spin axis 207 which is not further detailed in the figures. Specifically, the microfluidic device 202 can be rotated in opposite direction compared to the substrate 206 so as to obtain a combined effect in rotating both the microfluidic device 202 and the substrate 206.
The substrate 206 faces the microfluidic device 202 keeping a small inter-distance. Furthermore, the substrate 206 is provided with plural step-like protrusions 208 radial extending from an outer perimeter of the disk-like substrate 206 to the central spin axis 207 and projecting towards the microfluidic device 202, one of which is shown in a sectional perspective view directed to the central spin axis 207 for the purpose of illustration only. Stated more particularly, the substrate 206 includes lower substrate sections 209 projecting to a lesser extent towards the microfluidic device 202 alternating with higher substrate sections 210 projecting to a greater extent towards the microfluidic device 202.
As a matter of fact, in case of having a sufficiently small inter-distance between the substrate 206 and the device 202 which, e.g., is on the order of millimetres or less, a positive pressure can be generated in an intermediate zone 211 in-between the substrate 206 and the microfluidic device 202 as the substrate 206 rotates. As illustrated in FIG. 5B, the generated positive pressure p (x) has a maximum value at each changeover 212 between the lower substrate section 209 and the higher substrate section 210 and decreases in circumferential direction (x) away from the changeover 211. Those of skill in the art are aware of the physical mechanism of pressure generation by step-like protrusions 208 ("Rayleigh step bearing") so that it is not further elucidated herein. The ports 204 of the microfluidic structures 203 opening at the lower face 205 communicate with the intermediate zone 211 to, e.g., make air flow into the microfluidic structures 203 via the ports 204 to thereby generate a positive pressure in the microfluidic structures 203. As a result, liquid fluid contained in the microfluidic structures 203 can be pushed away from the ports 204. Otherwise, the microfluidic device 202 can also be rotated around the spin axis 207 in an opposite direction compared to the rotational direction of the substrate 206 to thereby increase the generated pressure. Furthermore, instead of generating a positive pressure, a negative pressure could also be generated according to the specific demands of the user by modifying the substrate 206 and/or changing the rotational direction of the substrate 206 and/or of the microfluidic device 202 and/or of both.
Another exemplary embodiment of the system according to the invention is illustrated generally at 301 in FIG. 6A depicting a sectional view and FIG. 6B depicting a partly sectional perspective view.
Accordingly, the system 301 comprises a disk-like microfluidic device 302 provided with plural microfluidic structures 303 one of which is shown for the purpose of illustration only. The plural microfluidic structures 303 are circumferentially arranged with respect to each other similar to the embodiment of FIGS. 5A and 5B. Each of the microfluidic structures 303 includes a fluid zone 304 opening to the atmosphere via a first port 305 for introducing liquid fluid to the microfluidic structure 303 at an upper face 312 of the microfluidic device 302. It further includes an essentially U-shaped flow channel 306 in fluid communication with the fluid zone 304 and a second port 307 which opens at a lower face 308 of the microfluidic device 302.
The system 301 further includes a disk-like support 309 provided with an upper planar supporting face 310 adapted for supporting the microfluidic device 302. The support 309 can be spun around a spin axis 311, e.g., by means of an electrically driven motor or a centrifuge. The microfluidic device 302 co-rotates with the support 309. Specifically, the flow channel 306 of the microfluidic structure 303 includes a radial outermost portion 313 relative to the spin axis 311. The flow channel 306 includes a first portion 324 and a second portion 325, both of which having a radial-inner position compared to the radial outermost portion 313 adjacent the radial outermost portion 313. In this exemplary embodiment, the first port 305 has a radial-inner position compared to the second port 307. Otherwise, the second port 307 has a radial-inner position compared to the radial outermost portion 313 of the flow channel 306 relative to the spin axis 311.
In the system 301, the support 309 is provided with plural cavities, e.g., embodied as ducts 314 formed in the support 309, the number of which corresponds to the number of microfluidic structures 303. In that, each of the ducts 314 communicates with one of the second ports 307 opening at the lower face 308 of the microfluidic device 302. Otherwise, the ducts 314 are in fluid communication with one pump (not illustrated) for generating a positive and/or negative pressure therein. Stated more particularly, each of the ducts 314 communicates with a (central) coupling conduit 316 of a rotary coupling 315 connected to the pump and rotationally decoupling the pump from the support 309. In the system 301, the microfluidic structure 303 communicates with one first port 305 and one second port 307. The microfluidic structure 303 may further communicate with at least one vent for transferring gaseous liquid such as air into/out of the microfluidic structure 303. In the system 301, each microfluidic structure 303 communicates with one individual first port 305 and one individual second port 307. Otherwise, while not shown, more than one microfluidic structures 303 may communicate with one common first port 305 and/or one common second port 307 so that each of the ports 305, 307 communicates with plural microfluidic structures 303. In the system 301, e.g., the first port 305 is being used for introducing liquid fluid into the microfluidic structure 303 while the second port 307 is being used for generating a positive and/or negative pressure in the microfluidic structure 303. Specifically, the second port 307 can also be used for introducing and/or withdrawing liquid fluid into/out of the microfluidic structure 303.
Hence, in the system 301, the duct 314 is connected to the pump so that gaseous and/or liquid fluid can be transferred to/out of the microfluidic structure 303. Hence, the pump can, e.g., be embodied as a gaseous and/or liquid fluid pump adapted for pumping gaseous and/or liquid fluids. Specifically, liquid fluid can be introduced into the microfluidic structure 303 in a dosed manner, e.g., while rotating the microfluidic device 302 around the spin axis 311 regardless of the rotational speed of the support 309. Otherwise, using the pump, cooling and/or heating fluid such as water can be circulated within the support 309 for transferring heat (thermal energy) to/from the liquid fluid contained in the microfluidic structure 303. While not shown in the figures, a thermal intermediate member (thermal interface) having good thermal conductivity can be placed in-between the support 309 and the microfluidic device 302 in order to obtain an improved heat transfer between the duct 314 and the microfluidic structure 303 via such intermediate member.
Using the system 301 of FIGS. 6A-6B, a method for manipulating liquid fluids includes a step of introducing liquid fluids into the fluid zones 304 of the microfluidic structures 303 via the first ports 305, followed by spinning the support 309 around the spin axis 311, the microfluidic device 302 co-rotating therewith. Spinning the support 309 generates a centrifugal force to transport the liquid fluids from the fluid zones 304 to the first and second portions 324, 325 adjacent the radial outermost portion 313 of the flow channel 306. Then, by generating a positive or negative pressure in the microfluidic structures 303 via the second ports 307 by withdrawing air out of the flow channels 306, at least portions of the liquid fluids contained in the flow channels 306 are transported to radial-inner positions relative to the spin axis 311 counteracting the centrifugal force. By releasing the positive or negative pressure, the liquid fluids are transported to radial more outward positions by effect of the centrifugal force. Hence, the liquid fluids can be transported back and forth in the flow channels 306 as indicated by a double arrow 317. This bidirectional transport of the liquid fluids can be multiply repeated according to the specific demands of the user in order to mix the liquid fluids. Otherwise, by applying a positive or negative pressure at the second ports 307, portions of the liquid fluids can also be separated from the remainder and can be selectively removed from the microfluidic structures 303. Alternatively, liquid fluid can be transferred into the flow channels 306 via the second ports 307 in a dosed manner, e.g., while spinning the microfluidic device 302.
Referring to FIG. 7A depicting a sectional perspective view and FIGS. 7B and 7C depicting perspective bottom views, another exemplary embodiment of the system 301 according to the invention is explained. In order to avoid unnecessary repetitions, only differences with respect to the embodiment of FIGS. 6A und 6B are explained and, otherwise, reference is made to explanations given in conjunction therewith.
Accordingly, the support 309 supporting the microfluidic device 302 is provided with plural ducts 314 the number of which corresponds to the number of second ports 307 of the microfluidic structures 303 wherein each of the ducts 314 communicates with an individual second port 307 at the lower face 308 of the microfluidic device 302. Otherwise, each of the ducts 314 is in fluid communication with a pump (not illustrated) by means of an individual coupling conduit 316 of the rotary coupling 315. The coupling conduits 316 can be connected to one or more pumps. Specifically, each of the coupling conduits 316 can be connected to an individual pump so that positive and/or negative pressures different with respect to each other can be simultaneously generated in the ducts 314. Otherwise, various amounts of gaseous and/or liquid fluid can be transferred to/from the microfluidic structures 303 via the second ports 307 according to the specific demands of the user. The flow channel 306 of an individual microfluidic structure 303 can, e.g., be connected to plural second ports 307 in parallel arrangement with respect to each other as illustrated in FIG. 7B. Specifically, one first port 305 can be connected to plural second ports 307 by one flow channel 306 bifurcating (dividing) into plural channel branches 318, each of which communicating with one second port 307. Alternatively, as illustrated in FIG. 7C, the flow channel 306 of an individual microfluidic structure 303 can also be connected to plural second ports 307 in serial arrangement with respect to each other.
Using the system 1 of FIGS. 7A-7C, a method for manipulating liquid fluids includes a step of introducing liquid fluids into the fluid zones 304 of the microfluidic structures 303 via the first ports 305, followed by spinning the support 309 around the spin axis 311 so that the microfluidic device 302 co-rotates with the support 309 to generate a centrifugal force to transport the liquid fluids from the fluid zones 304 to the first and second portions 324, 325 adjacent the radial outermost portion 313 of the flow channels 306. Positive and/or negative pressures which are similar or different with respect to each other can be generated in the microfluidic structures 303 via the second ports 307 so that at least portions of the liquid fluids can be transported to inner positions relative to the spin axis 311 counteracting the centrifugal force.
Reference is made to FIG. 8 depicting a schematic sectional view illustrating another exemplary embodiment of the invention. In order to avoid unnecessary repetitions, only differences with respect to the embodiment of FIGS. 6A-6B are explained and, otherwise, reference is made to explanations given in conjunction therewith.
Accordingly, the system 301 includes a heating and/or cooling foil 319 placed in-between the support 309 and the microfluidic device 302. The heating and/or cooling foil 319 is connected to a power supply and adapted to produce and/or adsorb heat which then is transferred to the microfluidic device 302 so that liquid fluid contained therein can be heated and/or cooled. The heating and/or cooling foil 319 may, e.g., include one or more Peltier devices. Otherwise, the system 301 includes plural cooling fins 320 which, when rotating the support 309, can efficiently cool the microfluidic device 302. Hence, liquid fluid contained in the microfluidic device 303 can be heated or cooled according to the specific demands of the user. Specifically, liquid fluid can be cycled through a series of temperature excursions in which predetermined temperatures are kept constant for specific time intervals. Accordingly, nucleic acid containing fluids can be repeatedly put through a sequence of amplification steps, e.g., based on the well-known polymerase chain reaction (PCR) which includes melting the nucleic acids to obtain denaturated single polynucleotide strands, annealing short primers to the strands, and extending these primers to synthesize new polynucleotide strands along the denaturated strands to make new copies of double-stranded nucleic acids.
Another exemplary embodiment of the system according to the invention is illustrated generally at 401 in FIG. 9A depicting a sectional view and FIG. 9B depicting a perspective bottom view.
Accordingly, the system 401 comprises an e.g. disk-like microfluidic device 402 provided with plural microfluidic structures 403 as above-described in conjunction with FIGS. 6A and 6B. In order to avoid unnecessary repetitions, reference is made to explanations given in conjunction therewith.
The system 401 includes an electric motor 404 having a rotationally driven shaft 405 provided with a fixedly secured supporting plate 406. An upper plate face 407 of the supporting plate 406 supports the microfluidic device 402 so that the microfluidic device 402 co-rotates with the supporting plate 406. Specifically, the microfluidic device 402 is provided with a central bore 408 penetrated by a pin 409 secured to the shaft 405 in order to fix the microfluidic device 402 to the shaft 405. Accordingly, the microfluidic device 402 can be spun around the spin axis 410 as defined by the shaft 405.
The system 401 further includes a pot-like open-top pressure chamber 411 having a planar bottom wall 412 and a cylindrical side wall 413 surrounding a cavity 414. The pressure chamber 411 and the microfluidic device 402 are rotationally decoupled so that the microfluidic device 402 can be rotated relative to the pressure chamber 411. The bottom wall 412 of the pressure chamber 411 is provided with a central shaft opening 415 penetrated by the shaft 405. As can be taken from FIG. 9A, the microfluidic device 402 is being adapted to entirely cover the cavity 414. A ring-like sealing lip 416, e.g., made of rubber, is arranged in-between the side wall 413 and the microfluidic device 402 to air-tightly seal the cavity 414. The side wall 413 is provided with a pipe connector 417 fluidically connected to a pump (not illustrated) for generating a positive and/or negative pressure in the cavity 414.
In case of generating a negative pressure in the cavity 414, the microfluidic device 402 is drawn onto the sealing lip 416 of the side wall 413 of the pressure chamber 411 which improves the sealing effect. Otherwise, a negative pressure of the cavity 414 generates a negative pressure in each of the microfluidic structures 403 via second ports 418 communicating with the pressure chamber 411 to suck liquid fluids contained therein to the second ports 418. Alternatively, a positive pressure could be generated in the cavity 414 to thereby generate a positive pressure in the microfluidic structures 403 to push liquid fluids contained therein away from the second ports 418. In that case, the pressure chamber 411 is provided with a counter bearing (not illustrated) to prevent an undesired uplift of the microfluidic device 402 from the pressure chamber 411.
Using the system 401 of FIGS. 9A-9B, a method for manipulating liquid fluids includes a step of introducing liquid fluids into the microfluidic structures 403 via the first ports, followed by a step of spinning the microfluidic device 402 to generate a centrifugal force to transport the liquid fluids to the first and second portions of the flow channels adjacent the radial-outermost portion thereof. Then, by generating a positive or negative pressure in the cavity 414 of the pressure chamber 411, a positive and/or negative pressure is generated in each of the microfluidic structures 403 via the second ports 418 so that at least a portion of the liquid fluids contained therein is transported to an inner position relative to the spin axis 410 counteracting the centrifugal force.
Reference is made to FIGS. 10A-410E depicting schematic sectional views illustrating variants of the system 401 of FIGS. 9A-9B. Accordingly, with particular reference to FIG. 10A, the cylindrical side wall 413 of the pressure chamber 411 has no sealing lip 416. Instead, a small circular slit 419 is kept in-between the microfluidic device 402 and the side wall 413 so that there is no direct contact between the microfluidic device 402 and the pressure chamber 411. Furthermore, instead of providing for the pipe connector 417, the bottom wall 412 of the pressure chamber 411 is provided with a fan opening 420 enabling a fan 421 to generate a positive and/or negative pressure in the cavity 414.
With particular reference to FIG. 10B, the cylindrical side wall 413 of the pressure chamber 411 is provided with an O-ring seal 422 contacting a lower face 423 of the microfluidic device 402.
With particular reference to FIG. 10C, a diameter of the cylindrical side wall 413 of the pressure chamber 411 is smaller than a diameter of the microfluidic device 402.
With particular reference to FIG. 10D, the cylindrical side wall 413 of the pressure chamber 411 is provided with a downwardly extending sealing lip 416 which contacts an end face 424 of the microfluidic device 402.
With particular reference to FIG. 10E, the cylindrical side wall 413 of the pressure chamber 411 is provided with an upwardly extending sealing lip 416 which is sideward curved to contact the end face 424 of the microfluidic device 402.
Referring to FIG. 11 depicting a sectional view, another exemplary embodiment of the system 401 according to the invention is explained. In order to avoid unnecessary repetitions, only differences with respect to the embodiment of FIGS. 9A and 9B are explained and, otherwise, reference is made to explanations given in connection therewith.
Accordingly, the open-top pressure chamber 411 is provided with a cylindrical inner separating wall 425 dividing the cavity 414 into an inner ring cavity 426 and an outer ring cavity 427. Each of the inner and outer ring cavities 426, 427 is provided with an individual pipe connector 417 so that different positive and/or negative pressures can be generated in the inner and outer ring cavities 426, 427. The inner ring cavity 426 communicates with an individual first set of second ports 418 while the outer ring cavity 427 communicates with an individual second set of second ports 418 different from the first set. Accordingly, in a method for manipulating liquid fluids, positive and/or negative pressures which are similar or different with respect to each other can be generated via the first and second sets of second ports 418 according to the specific demands of the user.
Referring to FIGS. 12A-12B another exemplary embodiment of the system 401 according to the invention is explained. FIG. 12A depicts a sectional perspective view of the system 1, FIG. 12B an enlarged detail thereof according to the dashed line. In order to avoid unnecessary repetitions, only differences with respect to the embodiment of FIGS. 10A-10B are explained and, otherwise, reference is made to explanations given in conjunction therewith.
Accordingly, the rotatable microfluidic device 402 is provided with a central recess 428 for receiving a means to introduce liquid fluid into the microfluidic structure 403 such as a fleece pad 429 which can be soaked with blood 430 of a patient's finger 431. The fleece pad 429 can be put into the central recess 428 e.g. centred by a pin 432. A foil 433 may be placed on an upper side of the fleece pad 429 for air-tightly sealing the fleece pad 429. The microfluidic device 402 further includes plural through-holes 434 which are covered by the foil 433. Accordingly, in case of generating a negative pressure in the cavity 414, the foil 433 is drawn onto the upper face 435 of the microfluidic device 402 to thereby fix the fleece pad 429. When rotating the microfluidic device 402 around the spin axis 410, the blood 430 or fractions thereof contained in the fleece pad 429 can be centrifuged into the microfluidic device 402 via fluid ducts 436 communicating with the central recess 428. Additionally or alternatively, a negative pressure can be generated in the microfluidic structures 403 to thereby suck the blood 430 via the fluid ducts 436 in. Yet alternatively, dedicated ports communicating with the microfluidic structures 403 and opening into the central recess 428 can be envisaged to push the blood 430 out of the fleece pad 429 by generating a positive pressure in the microfluidic structures 403.
The system 401 of FIGS. 12A-12B will be especially useful for the separation of blood plasma. Stated more particularly, in case the fleece pad 429 is adapted to retain cellular components of the blood 430, when rotating the microfluidic device 402, blood plasma can be selectively centrifuged into the microfluidic device 402. Additionally or alternatively, a positive and/or negative pressure as-above detailed can be used to separate the blood plasma from the cellular blood fraction.
Reference is made to FIGS. 13A-13B depicting schematic sectional views illustrating a method of activating the pressure-driven fluid transport in the microfluidic structure in the system 301 according to the invention.
Accordingly, the system 301 includes a porous fleece layer 321 in-between the support 309 and the microfluidic device 302 which are in stacked relationship with respect to each other. The fleece layer 321 and the microfluidic device 302 e.g. are being provided with a through hole 322 which is in fluid communication with the duct 314 of the support 309. Accordingly, the duct 314 opens to the atmosphere via the porous fleece layer 321 and optionally also via the through-hole 322.
Specifically, FIG. 13A depicts a situation in which the duct 314 is open to the atmosphere so that in case of generating a positive and/or negative pressure in the duct 314, due to the leakage by the through-hole 322 only a small or even zero pressure-driven fluid transport will occur. Otherwise, as depicted in FIG. 13B, in case of covering the duct 314 by a covering foil 323 on the upper face 312 of the device 302, a large pressure-driven fluid transport can be obtained. Accordingly, by applying or removing the covering foil 323, activation or deactivation of the liquid fluid transport can readily be obtained. While not illustrated, the method of activating the pressure-driven liquid fluid transport could also be used in the various systems as-above detailed.
Reference is made to FIGS. 14A-14C depicting schematic top views to illustrate a method of separating and mixing liquid fluids which can be used in any one of the various systems according to the invention. Accordingly, each microfluidic structure 503 includes a first cuvette 504 and a second cuvette 505 communicating by an inter-cuvette conduit 506. Specifically, the first cuvette 504 includes a first chamber 507 and a second chamber 508 communicating by an inter-chamber conduit 509. More specifically, the first chamber 507 communicates with a first port 510 and the second cuvette communicates with a second port 511 via a port conduit 512. The inter-cuvette conduit 506 communicates with the inter-chamber conduit 509 at an intersection 513. In the microfluidic structure 503, the first port 510 is at a radial-inner position as to the first cuvette 504, the second cuvette 505 is at a radial-inner position as to the first cuvette 504, and the second port 511 is at a radial-inner position as to the second cuvette 505 relative to the spin axis (not illustrated).
The microfluidic structure 503 of FIG. 14A will be especially useful for separating and mixing methods. Stated more particularly, FIG. 14A illustrates a situation in which liquid fluid such as whole blood has been introduced through the fluid port 510 into the microfluidic structure 503, followed by applying centrifugal force by rotating the microfluidic device 502 to separate the blood into a blood plasma fraction 514 and a cellular fraction 515 mainly containing erythrocytes, leucocytes and thrombocytes. Open to the ambient, the atmospheric pressure acts on the fluid port 510.
FIG. 14B depicts a situation in which, while spinning the microfluidic device 502 a negative pressure is applied to the second port 511. As a result, the blood plasma fraction 514 is sucked into the second cuvette 505. While transferring the fluid, a fluid level of the first cuvette 504 is lowered.
FIG. 14C depicts a situation in which, while spinning the microfluidic device 502, the negative pressure is released so that the blood plasma fraction 514 contained in the second cuvette 505 is driven back to the first cuvette 504 by the centrifugal force resulting in a rise of the fluid level of the first cuvette 504. Due to the high rotational speed of the microfluidic device 502, a rather high flow rate of the blood plasma fraction 514 flowing back to the first cuvette 504 can be obtained. As a result, chaotic mixing of the liquid in the first cuvette 504 can occur so that a reliable, safe and quick mixing of the liquid fluid can be obtained.
While not illustrated in FIGS. 14A-14C, the blood plasma fraction 514 could alternatively be removed from the microfluidic structure 503 via the second port 511. In FIGS. 14A-14C, the first port 510 can be used to introduce liquid fluid into the microfluidic structure 503 while the second port 511 can be used to generate a positive and/or negative pressure therein. Reference is made to FIG. 15 illustrating another method of separating and mixing the liquid fluid contained in the microfluidic structure 503 of FIGS. 14A-14C. Accordingly, the whole blood is transferred into the first cuvette 504 and separated into the blood plasma fraction 514 and the cellular fraction 515 by centrifugal force created as the microfluidic device 502 is rotated. Then, while continuing to spin the microfluidic device 502, a negative pressure is applied to the pressure port 511 so that a portion of the blood plasma fraction 514 is sucked into the second cuvette 505 until the first chamber 507 of the first cuvette 504 and at least a portion of the inter-chamber conduit 509 are void of any liquid fluid. As a result, air is sucked into the second cuvette 505 so that air bubbles 516 are urged to pass through the blood plasma fraction 514 contained in the second cuvette 505. After that, while continuing to spin the microfluidic device 502, the negative pressure is suddenly released so that the blood plasma fraction 514 contained in the second cuvette 505 is driven back to the first cuvette 504 by the centrifugal force to then start a mixing method as above described in connection with FIGS. 14A-14C.
Accordingly, as-above detailed, two different effects can advantageously be used for mixing liquid fluids contained in the microfluidic structures 503, i.e., a first effect of having a rapid back-flow of liquid fluid from the second cuvette 505 to the first cuvette 504 and a second effect of making air bubbles 516 pass through the liquid fluid contained in the second cuvette 505. The first and second effects can be individually applied or can be used in combination for mixing liquid fluids contained in the microfluidic structure 503.
Reference is made to FIG. 16, a schematic sectional view illustrating a method of making liquid fluids flowing through a cuvette which can be used in any one of the various systems according to the invention.
Accordingly, a microfluidic structure 603 includes a single cuvette, in the following denoted as flow-through cuvette 604. The flow-through cuvette 604 is connected to a second port 605 by means of a port conduit 606. The second port 605 may be used to generate a positive and/or negative pressure in the microfluidic structure 603. Otherwise, a cuvette inlet conduit 607 communicates with the flow-through cuvette 604 at a radial-inner position while a cuvette outlet conduit 608 communicates with the flow-through cuvette 604 at a radial-outer position relative to the spin axis (not shown). The microfluidic structure 603 of FIG. 16 can be used as flow-through pump. Stated more particularly, while spinning the microfluidic device to generate a centrifugal force which is indicated by an arrow 609, a negative pressure is applied to the second port 605. As a result, liquid fluid is sucked from the cuvette inlet conduit 607 to an inlet 610 and then enters into the flow-through cuvette 604. In the flow-through cuvette 604, the liquid fluid is centrifuged towards an outlet 611 and flows away via the cuvette outlet conduit 608.
In the microfluidic structure 603, due to a difference in density, the liquid fluid can be driven to an outer position when sufficient remaining air is present in the flow-through cuvette 604. Given a sufficiently high "liquid column" in the cuvette outlet conduit 608, a negative pressure in the flow-through cuvette 604 can be reduced or even switched off resulting in a transport of the liquid fluid in the flow-through cuvette 604 caused by the mass of the liquid column (principle of communicating tubes). This method can be multiply repeated. Accordingly, using the method as above-explained, liquid fluid can be transferred from one cuvette to another cuvette without a need to separate the cuvettes by geometric valves. Moreover, each of the cuvettes can be placed in a radial-outer position with respect to the previous cuvette.
Reference is made to FIG. 17 depicting a schematic sectional view illustrating a method of cooling liquid fluids which can be used in any one of the various systems according to the invention.
Accordingly, a microfluidic structure 703 includes a single cuvette, in the following denoted as cooling cuvette 704. The cooling cuvette 704 is connected to a second port 705 by means of a port conduit 706. The second port 705 may be used to generate a positive and/or negative pressure in the microfluidic structure 703. Otherwise, an inlet conduit 707 communicates with the cooling cuvette 704 to fill the cooling cuvette 704 with liquid fluid. In the microfluidic structure 703, in case of having liquid fluid filled in the cooling cuvette 704 by applying a negative pressure at the second port 705, while continuously spinning the microfluidic structure 703, the negative pressure is kept for a predetermined time interval in order to cool the liquid fluid in the cooling cuvette 704 by evaporation heat. Stated more particularly, evaporation of the liquid fluid is caused by the negative pressure which results in cooling of the liquid fluid since evaporation of the liquid fluid requires energy which is taken from the liquid fluid. Specifically, equilibrium between the centrifugal force and the suction force acting on the liquid fluid has to be reached. The cooling efficiency can be increased by increasing pressure and/or enlarging the surface of the liquid fluid.
In the systems of the invention, a positive and/or negative pressure can be selectively generated or released without any limitation as to the rotational frequency of the microfluidic device. As a matter of fact, in the systems of the present invention, positive and/or negative pressures can be generated while rotating the microfluidic device at comparably small rotational frequencies or even in case of standstill. As a major advantage, the systems of the present invention offer an alternative to the use of geometric fluid valves which can be broken by a critical centrifugal force, Since there is no valve-specific limitation of the rotational frequency, the microfluidic device can be rotated at higher rotational frequencies resulting in better control of the transported fluid volumes, less wetting of inner walls of the microfluidic structures and less carry-over (contamination) in case of multiple use of the microfluidic structures. The systems of the present invention thus offer reliable triggering of fluid transport, so that reliability of reactions can be improved due to better dosing. Otherwise, contrary to the use of geometric fluid valves requiring precisely controlled critical centrifugal forces, frequency control can be less precise enabling less sophisticated motors to be used for spinning the microfluidic device.
Furthermore, in the system of the invention, by generating a positive and/or negative pressure, liquid fluid contained in the microfluidic structures can be transported from a radial-outer position to an radial-inner position relative to the spin axis. Conventional centrifugal force-driven transport enables transport only from a radial-inner position to a radial-outer position relative to the spin axis. Since liquid fluid may not splash out, contamination of fluids can advantageously be avoided.
With respect to capillary effect-based fluid transport, flow rates can be highly increased. Hence, process times, transfer times and/or reaction times of the liquid fluids can advantageously be reduced. Otherwise, in contrast to capillary-based channels which typically require the microfluidic device be formed of hydrophilic material, in the systems of the present invention, the microfluidic device can be formed of non-hydrophilic material enabling that a wide variety of materials can be used for manufacturing the microfluidic device.
In the systems of the present invention, generation of positive and/or negative pressures for transporting liquid fluids can also be performed while spinning the microfluidic device around the spin axis (i.e. on the fly). Multiplexing of positive and/or negative pressures can be obtained by plural ducts connected to individual pressure generating means.
Reference list

101: System
102: Microfluidic device
103: Microfluidic structure
104: Port
105: Flow channel
106: Fan
107: Air duct
108: Nozzle
109: Air stream
110: Air guiding face
111: Arrow
112: Upper face
113: Spin axis
114: Arrow
201: System
202: Microfluidic device
203: Microfluidic structure
204: Port
205: Lower face
206: Substrate
207: Spin axis
208: Protrusion
209: Lower substrate section
210: Higher substrate section
211: Intermediate zone
212: Changeover
301: System
302: Microfluidic device
303: Microfluidic structure
304: Fluid zone
305: First port
306: Flow channel
307: Second port
308: Lower face
309: Support
310: Supporting face
311: Spin axis
312: Upper face
313: Outermost portion
314: Duct
315: Rotary coupling
316: Coupling conduit
317: Arrow
318: Channel branch
319: Heating and/or cooling foil
320: Cooling fin
321: Fleece layer
322: Through-hole
323: Covering foil
324: First portion
325: Second portion
401: System
402: Microfluidic device
403: Microfluidic structure
404: Motor
405: Shaft
406: Supporting plate
407: Plate face
408: Bore
409: Pin
410: Spin axis
411: Pressure chamber
412: Bottom wall
413: Side wall
414: Cavity
415: Shaft opening
416: Sealing lip
417: Pipe connector
418: Second port
419: Slit
420: Fan opening
421: Fan
422: O-Ring
423: Lower face
424: End face
425: Separating wall
426: Inner ring cavity
427: Outer ring cavity
428: Recess
429: Fleece pad
430: Blood
431: Finger
432: Pin
433: Foil
434: Through-hole
435: Upper face
436: Fluid duct
503: Microfluidic structure
504: First cuvette
505: Second cuvette
506: Inter-cuvette conduit
507: First chamber
508: Second chamber
509: Inter-chamber conduit
510: First port
511: Second port
512: Port conduit
513: Intersection
514: Blood plasma fraction
515: Cellular fraction
516: Air bubble
603: Microfluidic structure
604: Flow-through cuvette
605: Second port
606: Port conduit
607: Cuvette inlet conduit
608: Cuvette outlet conduit
609: Arrow
610: Inlet
611: Outlet
703: Microfluidic structure
704: Cooling cuvette
705: Pressure port
706: Port conduit
707: Inlet conduit
708: Fluid

Claims

A method for manipulating liquid fluids in a microfluidic structure, comprising the following steps of:
introducing said liquid fluid through one first port into said structure;

making air to either flow across said first port or a second port being different from the first port and communicating with the microfluidic structure to generate a negative pressure in said structure and/or to at least partially flow into said port to generate a positive pressure in said structure;

spinning said microfluidic structure around a spin axis to generate a centrifugal force acting on said liquid fluid contained in said microfluidic structure.
The method according to claim 1, comprising the following steps of:
spinning said microfluidic structure around said spin axis to generate a centrifugal force so as to transport said liquid fluid in a first direction having at least a directional component along said centrifugal force;

generating a positive and/or negative pressure in said microfluidic structure, said pressure acting on said liquid fluid in a manner to transport said liquid fluid in a second direction, said second direction being identical or different to said first direction and having at least a directional component along or opposite to said centrifugal force.
The method according to claims 1 or 2, in which generation of said positive and/or negative pressure is maintained for a predetermined time interval to make air bubbles flow through said liquid fluid in order to mix said liquid fluid contained in said microfluidic structure.
The method according to claims 2 or 3, which while spinning said microfluidic structure comprises a step of transporting said liquid fluid back and forth in which either said positive and/or negative pressure is generated in a manner that a force is created sufficient for outbalancing said centrifugal force so that said liquid fluid is transported to a radial-inner position or is reduced or stopped so that said centrifugal force transports said liquid fluid to a radial-outer position.
The method according to any one of the preceding claims 1 to 4, in which while spinning said microfluidic structure generation of said positive and/or negative pressure is maintained for a predetermined time interval so as to cool said liquid fluid by evaporating fluid in a controlled manner and/or to phase-change said liquid fluid from one aggregate condition to another in a controlled manner.
A system (301) for manipulating liquid fluids, comprising:
a microfluidic device (302) provided with at least one microfluidic structure (303) communicating with at least one port (305, 307) for introducing said liquid fluid into said structure (303), a support (309) for supporting said microfluidic device (302) which can be spun around a spin axis (311) to generate a centrifugal force acting on said liquid fluid, said support (309) being provided with at least one duct (314) communicating with said port (305, 307) and being connected to a pump for transferring gaseous and/or liquid fluid from and/or to said microfluidic structure (303) and/or for circulating cooling and/or heating fluid within said support for transferring heat from and/or to said liquid fluid contained in said microfluidic structure (303).
The system (301) according to claim 6, further comprising a rotary coupling (315) inter-connected between said duct (314) and said pump.
The system (301) according to any one of the preceding claims 6 or 7, further including a heating and/or cooling device (319) arranged in-between said support (309) and said microfluidic device (302) for heating and/or cooling said liquid fluid contained in said microfluidic structure (303).
A system (401) for manipulating liquid fluids, comprising:
a microfluidic device (402) provided with at least one microfluidic structure (403) communicating with at least one port for introducing said liquid fluid into said microfluidic structure (403), a spinning device (404, 405) for spinning said microfluidic device (402) around a spin axis (410),

an open-top chamber (411) adapted for covering by said microfluidic device (402), said chamber (411) being rotationally decoupled from said device (402), said chamber (411) including at least one cavity (414; 426, 427) communicating with said at least one port (418) and being connected to a pump for transferring gaseous and/or liquid fluid from and/or to said microfluidic structure (403).
A system (101) for manipulating liquid fluids, comprising:
a microfluidic device (102) provided with at least one microfluidic structure (103) communicating with at least one port (104) for introducing said liquid fluid into said microfluidic structure (103) at least one nozzle (108) adapted for ejecting an air stream (109), said nozzle (108) being operatively coupled to said port (104) so that said ejected air stream (109) is either made to flow across said port (104) to generate a negative pressure in said microfluidic structure (103) or is made to at least partially flow into said port (104) to generate a positive pressure therein.
The system (101) according to claim 10, wherein said nozzle (108) is being operatively coupled to an air guiding face (110) and being adapted to either guide said ejected air stream (109) across said port (104) or to guide at least a portion of said ejected air stream (109) into said port (104).
The system (101) according to any one of the preceding claims 10 or 11, further comprising a spinning device for spinning said microfluidic device (102) around a spin axis (113) to generate centrifugal force acting on said liquid fluid as the device (102) rotates.
A system (201) for manipulating liquid fluids, comprising:
a microfluidic device (202) which can be spun around a spin axis (207) provided with at least one microfluidic structure (203) communicating with at least one port (204) for introducing said liquid fluid into said microfluidic structure (203),

a substrate (206) facing said microfluidic device (202), wherein said substrate (206) and/or said device (202) being provided with one or more step-like protrusions (208) protruding towards said microfluidic device (202) and device (202), respectively, in a manner that a positive and/or negative pressure is generated in an intermediate zone (211) in-between said substrate (206) and said device (202) as the substrate (206) and/or the device (202) rotate around a spin axis (207), said port (204) communicating with said intermediate zone (211).
The system (101-401) according to any one of the preceding claims 6 to 9 and 12 to 13, wherein said microfluidic device is being provided with a recess (428) for receiving a means (429) to introduce said liquid fluid into the microfluidic structure (403).
The system (101-401) according to any one of the preceding claims 6 to 9 and 12 to 14, wherein said microfluidic device includes a first portion (324) and a second portion (325), both of which have a radial-inner position compared to a radial outermost portion (313) of the microfluidic structure relative to said spin axis around which said microfluidic structure can be spun.