WO2010091684A1

WO2010091684A1 - Analysis apparatus with degassing unit

Info

Publication number: WO2010091684A1
Application number: PCT/DK2009/000037
Authority: WO
Inventors: René Bogelund NYBERG
Original assignee: Danfoss Ventures AS
Current assignee: Danfoss Development AS
Priority date: 2009-02-10
Filing date: 2009-02-10
Publication date: 2010-08-19
Anticipated expiration: 2011-08-10

Abstract

The present invention relates to a flow construction adapted to degas a fluid, preferable flowing with micro-flow rates or less, where gas in the form of micro bubbles, possibly due to pressure reductions in the system, may block micro channels and hence destroy the flow in the specific applications. The idea is to introduce bubble generating and pressure reducing units (12) in fluid connection with a chamber (4), wherein at least part a of the walls enclosing the chamber is made of a gas permeable membrane (5). A filter (9) is positioned at the fluid outlet of the chamber inhibiting the bubbles from leaving the chamber with the rest of the fluid. The present invention further relates to an analysis apparatus introducing the flow construction.

Description

ANALYSIS APPARATUS WITH DEGASSING UNIT

The present invention relates to a flow construction adapted to degas a fluid, preferable flowing with micro-flow rates or less, where gas in the form of micro bubbles, possibly due to pressure reductions in the system, may block micro channels and hence destroy the flow in the specific applications. The idea is to introduce bubble generating and pressure reducing units in fluid connection with a chamber, wherein at least part a of the walls enclosing the chamber is made of a gas permeable membrane. A filter is positioned at the fluid outlet of the chamber inhibiting the bubbles from leaving the chamber with the rest of the fluid. The present invention further relates to an analysis apparatus introducing the flow construction.

BACKGROUND

It is a well known phenomenon and problem especially within the field of micro fluid devices, that bubbles may arise and block the fluid conduits of the micro fluid device. A number of ways have been introduced to inhibit the formation of bubbles, or to trap them before entering the critical parts of the devices, and possibly removing the gas from the bubbles when trapped.

One such device is for example seen in US2005266582A describing a microfluidic system for performing chemical reactions or biochemical, biological, or chemical assays utilizing a microfabricated device or "chip." The system may include, among others, an integrated membrane fabricated from a chemically inert material whose permeability for gases, liquids, cells, and specific molecules, etc. can be selected for ay optimum results in a desired application. The document shows in FIG. 6 a cross-sectional view of a microfluidic chip assembly 100a according to aspects of the present teachings. Substrate assembly 118a, i.e. a fabricated substrate is fabricated from substrate material 101a. Fabricated substrate 118a comprises an inlet access port 104a and an outlet access port 112a extending between a channel surface 103a and an access port surface 103b. A fluid channel 106a is located on channel surface 103a of substrate 101a, extending between inlet access port 104a and outlet access port 112a defining a channel floor surface 108a. A gas permeable membrane 110a is sealably attached to channel surface 103a of fabricated substrate 118a defining a membrane surface 108a within fluid channel 106a. Fluid 102a flows into inlet 104a, through fluid channel 106a where it passes between the channel floor 108a and membrane surface 109a and then exits through outlet 112a. Due to the relatively high gas permeability of the membrane and thin channel depth, exchange of gas 114 occurs between the fluid and the exterior environment of the chip. Bubbles formed in the channel during priming with fluid or in operation can escape through the membrane.

Another document US2008118790 uses bubbles actively and removes them again in a gas venting region, describing a bubble generator 14 generating multiple bubbles 16 or a "bubble train" within the channel 8. The bubble train produces pulsatile movement of the fluid within the channel 8.

In relation to the bubble generator, it is disclosed that the bubble generator 14 is disposed at or adjacent to the channel 8 and is used to generate a plurality of individual gaseous vesicles or bubbles 16 within the channel 8. The bubble generator 14 may be formed, for example, from one or more electrodes that generate bubbles form the electrolytic decomposition of the fluid contained within the channel 8. Alternatively, the bubble generator 14 may be formed from a heating element that creates vapor bubbles 16 from the fluid within the channel 8. In still another embodiment, the bubble generator 14 may be formed from a cavitation element. Bubbles 16 are generated by cavitation within the fluid. For example, the application of high frequency sound waves (e.g., ultrasonic energy) may be used as the cavitation source. In still another aspect, the bubble generator 14 may be formed from a gas injector. To remove the bubbles again from the system an optional one-way valve 18 may be introduced ensuring that the bubbles 16 are retained in the gas venting region of the device 2 which is covered by the venting membrane 20. The one-way valve 18 may be constructed as a partial obstruction of the channel 8 as is explained in detail above. The one-way valve may be formed, for example, from a smaller-sized or partially obstructed microchannel. In addition, a venting membrane is disposed over a portion of the passageway in or downstream of the bubble generating region. The bubbles are able to exit the liquid by passing through the porous venting membrane."

None of these documents, however, describes to remove gas in a fluid, when the gas has not yet formed into bubbles.

In relation to fluid analysers, they may be used for controlling chemical and biological processes, such as the treatment of sewage water. They may also be used for monitoring the amount or concentration of specific soluble matter contained in a fluid being analysed, e.g. the amount of calcium in water. This is sometimes desirable because the amount of calcium in water flowing in a washing machine has an influence on the amount of washing powder it is necessary to use.

US 5,672,319 discloses a fully functional analysing unit included within a fluid-tight housing of a dialyzer which is immersed in the medium to be analysed. An opening in the housing is closed by a dialysis membrane. A channel defining body cooperates with the membrane to define a flow channel. The unit includes a carrier fluid reservoir and a carrier pump for generating a flow of carrier fluid through the flow channel. The self-contained unit includes a carrier fluid reservoir and a carrier pump for generating a flow of carrier fluid through the flow channel to allow transfer of ions and molecules between a medium and the carrier fluid across a membrane. As a result, the flow of carrier fluid is transformed into a flow of sample fluid which is received in a reaction channel. Reagent fluid from at least one reagent reservoir is delivered to the reaction channel by at least one reagent pump, and a detection device is coupled to the reaction channel for detecting a reaction product originating from a reaction between the reagent fluid and the sample fluid and for generating a corresponding detection signal.

US 6,120,736 discloses an analysis apparatus for carrying out chemical analyses. The apparatus has a base member in which there is at least one channel, and it has at least one functional element which is in fluid or gaseous connection with the channel. Pumps are required to set the individual fluids moving in order to mix them with one another or to bring them to a different location.

All of the systems described above require pumps in order to operate properly. This means that the systems consume at least the amount of energy required to drive the pumps. Furthermore, in order to ensure a uniform mixture of sample fluid and reagent, which is required in order to obtain reliable measurements, the flows of sample fluid and reagent, respectively, must be controlled very accurately and in dependence of each other. Therefore relatively complex and precise control systems must be used for controlling the pumps, e.g. using some kind of feedback mechanism. This is cumbersome and relatively expensive, and it still leaves a risk that the obtained mixture of sample fluid and reagent is not completely uniform, thereby putting an upper limit on the obtainable accuracy of the measurements performed by the system.

SUMMARY

It is an object of the present invention to overcome problems with bubbles in microfluidic structures, or microfluid systems, preferably being a part of an analysis apparatus, which is solved by introducing a degassing unit comprising a fluid inlet and a first fluid conduit having a first fluid inlet and a first fluid outlet, the first fluid outlet having fluid connection with to a first chamber, wherein a first bubble generating device is situated between the first fluid inlet and the first chamber.

In order to remove trapped bubbles of gas, at least a part of the walls enclosing the first chamber is permeable to gas.

To prevent bubbles from entering the microfluid system , the degassing unit further comprises a second fluid conduit having a second fluid inlet fluidic connected to the first chamber, and a second fluid outlet, a filter is being situated between the first chamber and the second fluid outlet.

To enhance degassing even further, a second bubble generating device is situated between the second fluid inlet and the second fluid outlet, and the second fluid outlet of the second fluid conduit is in fluid connection with a second chamber, at least a part of the walls enclosing the second chamber being permeable to gas. The device then further comprises a third fluid conduit having a third fluid inlet and a third fluid outlet, a filter being positioned between the third fluid inlet and the third fluid outlet.

Depending on the task, the first and optionally the second bubble generating device may be used separately, combined in series or parallel to remove any unwanted micro bubbles, whether these are formed due to pressure reduction, chemical reaction or other bubble generating devices or phenomena or simply present in the fluid.

It is further an object of the invention to provide an analysis apparatus for analysing a fluid, in which more reliable measurements can be obtained than by using similar prior art apparatuses.

It is a further object of the invention to provide an analysis apparatus for analysing a fluid, in which uniform mixing of sample fluid and reagent can easily be ensured. It is an even further object of the invention to provide an analysis apparatus for analysing a fluid, in which the energy consumption is reduced as compared to similar prior art apparatuses.

It is an even further object of the invention to provide an analysis apparatus for analysing a fluid, in which the required maintenance to the apparatus is reduced as compared to similar prior art apparatuses.

According to the invention above and other objects are fulfilled by providing an analysis apparatus for analysing a fluid, the analysis apparatus comprising:

- a fluid communication system arranged in an interior part of the analysis apparatus, said fluid communication system providing fluid communication between parts of the analysis apparatus,

- a connector arranged to establish a fluid connection between a fluid medium having a first pressure, Pi, and the fluid communication system,

- a detection unit adapted to receive and mix sample fluid and reagent, analyze said mixed fluid and generate output, and

- at least one reagent container, each reagent container comprising a first volume for containing reagent, said first volume being fluidly connected to the detection unit and having a second pressure, P₂, and a second volume, said second volume being fluidly connected to the fluid communication system, said reagent container being arranged to deliver reagent in response to a pressure difference between the first volume and the second volume,

wherein a degassing unit as described above is arranged. In the present context the term 'analysis apparatus' should be interpreted to mean an apparatus which is adapted to perform analyses on a fluid medium, e.g. with respect to concentrations of certain substances, such as magnesium (Mg), calcium (Ca), biomolecules, bacteria, etc., present in the fluid.

The fluid to be analysed is preferably a liquid, but may, alternatively, be a gaseous fluid.

The fluid communication system provides fluid communication between parts of the analysis apparatus, e.g. via a system of pipes and/or tubes interconnecting the various parts in a desired manner.

The connector establishes a fluid connection between a fluid medium to be analysed and the fluid communication system. Thereby sample fluid is collected to the analysis apparatus, more specifically into the fluid communication system. Since the connector interconnects the fluid medium, having a first pressure, Pi, and the fluid communication system, the fluid communication system adapts the pressure of the fluid medium, Pi.

Accordingly, the pressure of the interior of the fluid communication system will fluctuate along with possible fluctuations of the pressure of the fluid medium.

The output generated by the detection unit preferably corresponds to the result of the analysis performed on the mixed fluid of sample fluid and reagent, e.g. indicating the amount of a specific substance of interest present in the fluid medium being analysed. The output may be in the form of an optical signal, an electrical current signal, a voltage signal, or any other suitable kind of signal. The reagent container comprises a first volume and a second volume. The first volume contains reagent and is fluidly connected to the detection unit, and thereby reagent can be delivered from the first volume of the reagent container to the detection unit. The first volume has a second pressure, P₂, which is also the pressure of an interior part of the detection unit, due to the connection between the first volume and the detection unit.

The detection unit may advantageously be connected to the exterior of the analysis apparatus, e.g. via an opening, preferably arranged in a sink for collecting used sample fluid. In this case the second pressure, P₂, is preferably at or near atmospheric pressure.

The second volume is fluidly connected to the fluid communication system, and thereby the pressure of the second volume is the same as the pressure of the fluid communication system, Pi. Since the second pressure is lower than the first pressure, P₂<Pi, a pressure difference exists between the first volume of the reagent container and the second volume of the reagent container, the higher pressure being in the second volume, and this pressure difference causes reagent to be delivered from the reagent container.

Simultaneously, the same pressure difference exists between the connector and the detection unit and is used for driving sample fluid to the detection unit via the fluid communication system. Accordingly, the ratio of the flow rate of sample fluid reaching the detection unit and the flow rate of reagent reaching the detection unit remains invariant, regardless of possible fluctuations in one or both of the pressures, Pi and P₂. Thus a reliable mixture, and thereby reliable measurements, is automatically obtained, and there is no need for complicated feedback mechanisms or the like. Furthermore, it is not necessary to use pumps in order to cause reagent and/or sample fluid to flow in the analysis apparatus, and energy can thereby be saved, and required maintenance of the apparatus can be reduced. The detection unit may comprise a mixing subsystem adapted to receive and mix sample fluid and reagent, and a separate detection part being fluidly connected to the mixing subsystem and being adapted to analyze the mixed fluid and to generate a corresponding output. According to this embodiment, sample fluid and reagent are received and mixed in a separate part of the detection unit, i.e. the mixing subsystem. Once the sample fluid and the reagent have been properly mixed, the mixed fluid is delivered to the detection part where it is analysed.

As an alternative, the detection unit may comprise only a single part in which the mixing of the reagent and the sample fluid, as well as the subsequent analysis takes place.

The fluid communication system may comprise at least one flow restrictor arranged in a flow path defined by the fluid communication system.

According to this embodiment, the flow rates of the fluid flows of various parts of the fluid communication system can be controlled by arranging flow restrictors of suitable flow resistance in selected parts of the fluid communication system.

According to one embodiment, at least one flow restrictor may be arranged in a part of the fluid communication system which fluidly interconnects the connector and the detection unit. According to this embodiment the flow rate of sample fluid reaching the detection unit is controlled. Alternatively or additionally, at least one flow restrictor may be arranged in a part of the fluid communication system which fluidly interconnects the connector and a waste chamber or a sink. A flow restrictor arranged in this manner ensures fast response times of the analysis apparatus.

Alternatively or additionally, the analysis apparatus may further comprise at least one flow restrictor arranged between the first volume of at least one reagent container and the detection unit. According to this embodiment the flow rate of reagent flowing from the reagent container to the detection unit is controlled.

At least one movable wall may separate the first volume and the second volume of at least one of the reagent containers. According to this embodiment the pressure difference between the first volume and the second volume causes the movable wall to move in such a manner that the first volume is 'squeezed'. Thereby reagent is squeezed out of the first volume and towards the detection unit. The movable wall may advantageously be in the form of a resilient wall. In this case the first volume may, e.g., be a bag or the like arranged inside the second volume.

The analysis apparatus may further comprise a pressure reduction system for reducing the first pressure, Pi, as compared to a pressure of an interior part of a flow system having a fluid medium to be analyzed flowing therein. Thereby the pressure difference defining the flow rates of sample fluid and reagent, respectively, can be reduced, and the flow rates can thereby be controlled. This is, e.g., an advantage in the case that the fluid medium has a relatively high pressure.

The pressure reduction system may comprise a reduction chamber with a compliance chamber having one or more movable walls arranged therein. The movable walls may, e.g., be in the form of walls made of a resilient material.

The analysis apparatus may further comprise at least one temperature controlling element. The viscosity of fluids is very often dependent on the temperature of the fluid. Thus, in order to control the flow rates of the sample fluid and the reagent, it is desirable to be able to control the temperature of the fluids flowing in the analysis apparatus. This can be obtained by arranging at least one temperature controlling element in the analysis apparatus. The temperature controlling element(s) may comprise a heating element and/or a cooling element.

In a further embodiment of the present invention, the second fluid conduit of the analysis apparatus is in fluid connection with the analysis section through a second sample fluid conduit, and a filter being in fluid connection withcis connected to the second sample fluid conduit.

Further, the second sample fluid conduit is in fluid connection with the second fluid condiut before the pressure reduction unit seen from the flow direction of flow in the second fluid conduit, the second outlet of the second fluid conduit being connected to externals. The filter preferable is attached in front of the inlet to the second sample fluid conduit.

The idea of this embodiment of the present invention is to ensure that the flow resistance through the flow path and the pressure reduction unit in the second fluid conduit is significantly lower than the flow resistance of the flow path through the filter, ensuring a significantly higher flow rate through the pressure reduction unit compared to the filter , easily 10-1000 times higher, most preferably in the order of 50-200 times higher.

The advantage of this design is that any micro bubbles formed after the first chamber will tend to take the path through the pressure reduction unit rather than through the filter, thus being removed from the system rather than entering the critical parts of the system in the analysis section. One further major advantage is that a filter filters the perfusion fluid for micro particles, and the fluid stream parallel to the filter running though the flow path of the pressure reduction unit helps to clean the filter to prevent clogging in time due to particles settling on the front side. FIGURES

Fig. 1 Illustration of a simple bubble trap.

Fig. 2 Illustration of the basic degassing unit of the present invention.

Fig. 3 Illustration of a more advanced degassing unit of the present invention.

Figs. 4 and 5 Illustration of degassing units of the present invention in a micro fluid chip.

Fig. 6 Illustration of a degassing unit of the present invention in a first embodiment of an analysis apparatus according to the present invention.

Figs. 7 Illustration of a degassing unit of the present invention in a second embodiment of an analysis apparatus according to the present invention.

Figs. 8 Illustration of a degassing unit of the present invention in a third embodiment of an analysis apparatus according to the present invention.

DETAILED DESCRIPTION

Fig. 1 is a simple illustration of the basics of the present invention. The figure shows a first fluid conduit (3) extending between a first fluid inlet and a first fluid outlet the first fluid outlet being in fluid connection with a first chamber (4), at least a part of the wall enclosing the first chamber (4) being permeable to air or gas but impermeable to fluid, being the gas permeable wall or gas permeable membrane (5). The gas permeable membrane (5) should consist of a non-wetting material which retains fluid but permits gas to diffuse through. It may be fixed either mechanically (lock ring, holding plate, etc..) or chemically (adhesive, plasma, etc..) to the substrate wherein the first chamber (4) is formed and on top of the first chamber (4). The pressure P₂ in the first chamber (4) should not exceed the water penetration limit for the gas permeable membrane (5).

A second fluid conduit (6) extending between a second fluid inlet and a second fluid outlet has the second fluid inlet in fluid connection with the first chamber (4). A filter (9) is positioned preferably between the second fluid inlet and the second fluid outlet, or inside the first chamber (4) in such a manner, that it covers the second fluid inlet. The filter (9) may be any filter known in the art, such as a membrane being perforated with milli- or nano- sized pores, only, it has to be passable to the fluid to flow in the system, but impassable to larger sized particles and the like, such as bubbles of gas (10).

A fluid flowing through the fluid device of the present invention is entering the first fluid inlet and flowing through the first fluid conduit (3), the first chamber (4), the second fluid conduit (6) and is leaving through the second fluid outlet (8), as it is illustrated with the arrows.

The filter (9) should have pore sizes of maximum but not limited to 10 μm, preferably less than 2 μm pore sizes. The relation between the pressure P and the maximum diameter of the pores of the filter, Dpore, ensuring that no bubbles are able to pass through the filter, is given by:

Dpore < (4γ ^* cos θ) / P = K1 / P,

where Y = Surface tension of the liquid, θ = Liquid-solid contact angle, P = bubble point pressure (P2 in the first chamber (4)), K1 = Empirical factor. The figure also illustrates a bubble (10) that has entered the first chamber (4). The bubble is too large sized to follow the fluid flow through the filter (8) and is thus constrained within the first chamber (4). In time the gas of the bubble (10) then diffuses (11) through the air permeable membrane (5) leaving the system altogether.

The problem, however, is that gas dissolved in the fluid, but not yet having been formed into bubbles will continue to flow with the fluid through the filter

(9).

The solution introduced in the present invention is to introduce or insert a first bubble generating and pressure reduction unit (12) at least partly positioned somewhere in the first fluid conduit (3) between the first fluid inlet and the fluid outlet, or alternatively at the inlet face of the first fluid inlet or at the outlet face of the first fluid outlet. Fig. 2 illustrates such a first bubble generating and pressure reducing unit (12) positioned partly in the first fluid conduit (3) having the first outlet section (13) reaching into the first chamber (4). This ensures a minimum dead volume in the system, but also, which is more important, it is ensured that all bubbles are formed inside the first chamber (4).

Water enters the system with an external pressure P1 and undergoes a pressure drop to P2 as it passes the pressure reduction unit (12). The pressure reduction from P1 to P2 causes dissolved gas in the water to degas and form bubbles by Henry's law which states: "the amount of air dissolved in a fluid is proportional with the pressure of the system".

The flow restriction of the combined flow system from inlet to and including the first chamber (4) in the direction of the fluid, shall preferably be less than the water penetration pressure for the gas permeable membrane (5) divided by the System flOW, FR < Ppenetratioπ, membrane / F_System- The first chamber (4) should be large enough to contain an incremental water volume with the bubble(s) trapped inside, without the bubble(s) having an impact on the continuous flow. If the degassing chamber (4) is too small, the formed bubble(s) can clog the entire flow system. The volume of the degassing chamber should follow but is not limited to the statement:

Vchamber > Vbubble,

where V_bUbbie is the volume of the bubble and is directly proportional to the inner diameter of the pressure reduction unit where the fluid flows and the outer diameter of the pressure reduction unit.

The second fluid conduit (6) preferably comprises a first small cavity (14) at the second inlet section, the first cavity (14) being a small section of the second fluid conduit (6) having a larger cross sectional area than the average cross-sectional area of the whole second fluid conduit (6). The second pressure reduction unit (16) is positioned between the second fluid inlet and the second fluid outlet. The purpose of the second pressure reduction unit (16) is to create a pressure P2 in the degassing chamber (4) that is high enough to force the generated micro bubbles out through degassing membrane (5), even at micro or nano flows (ul or nl / min) and also to diminish any diffusion of gas back through the gas permeable membrane (5), which will eventually form micro bubbles. If only a very small or no pressure P2 exists, the flow (micro or nano- flow) will not fill up the degassing chamber (4) and any dissolved gas in the water will be carried through filter (9) and further into the system where it can form micro bubbles.

The first cavity (14) ensures that the pressure drop across filter (9) is kept to a minimum and the area cross section of cavity (14) should follow, but is not limited to, the relation

(P2 - P3) → < Dpressure reduction unit (8) The statement says: The diameter of the bubble formed from the pressure reduction ΔP2-3 across the filter in volume formed by first cavity (14) and the second fluid conduit (6) due to Henry's law must not be bigger than the diameter of the inlet of the second pressure reduction unit (8). Otherwise the bubble will be big enough to influence, partially or completely block the pressure reduction unit (16).

The filter (9) may be positioned and fixed either mechanically (lock ring, holding plate, etc..) or chemically (Adhesive, plasma, etc..) on top of a small cavity (14).

Such a flow system comprising a first fluid conduit (3), a first bubble generating and pressure reducing unit (12), a first chamber (4) with a gas permeable membrane (5), a filter (9) positioned somewhere before a second fluid outlet containing a second pressure reduction unit (16) and a small cavity (14) , shall in the following be referred to as the basic degassing unit

(1).

In a more advanced version of the present invention, the second fluid conduit (6) has the second fluid outlet in fluid connection with a second chamber (15), at least a part of the wall enclosing the second chamber (15) being permeable to air or gas but impermeable to fluid, another gas permeable wall or membrane (23). This is an embodiment where at least two basic degassing flow systems are connected in series.

A second bubble generating and pressure reduction unit (17) is at least partly positioned somewhere in the second fluid conduit (6) between the second fluid inlet and the second outlet, or alternatively at the inlet face of the second fluid inlet positioned after the first filter (9), or at the outlet face of the second fluid outlet (18). Fig. 3 illustrates such a second bubble generating and pressure reducing unit (17) positioned partly in the second fluid conduit (6) having the first outlet section (18) reaching into the second chamber (15).

A third fluid conduit (20) extending between a third fluid inlet and a third fluid outlet has the third fluid inlet fluidic connected to the second chamber (15).

A second small cavity is optionally positioned at the third fluid inlet section (not shown), the second cavity formed as the first cavity (14) being a small section of the third fluid conduit (20) having a larger cross sectional area than the average cross-sectional area of the whole third fluid conduit (20).

The present embodiment illustrated in Fig. 3 shows a design with two chambers (4, 15) and with the corresponding fluid conduits (1 , 6, 20), gas permeable membranes (5, 23), filters (9, 19), small cavities (14) and bubble generating and pressure reduction unit (12, 17). However, any additional numbers of such basic degassing systems (1) may be introduced into the system of the present invention, either in series or in parallel, to form a degassing unit (2).

The second outlet in Fig. 2 and the third outlet in Fig. 3 are the outlets is where the fluid leaves the fluid device of the present invention, and would typically either be directly succeeded by the rest of the fluid system wherein the degassed fluid is to be used, or is connected thereto in any known manner in the art.

Figs. 4-6 illustrate the fluid device of the present invention in an embodiment where it is a built-in design in a flow system formed as channels in substrates, a fluid chip, or micro fluid chip when the flows in the system are in the range of microlitres per minute or less, the dimensions of the channels typically being in the range of micro meters or less. It is important to inhibit bubbles from entering the channels of especially micro fluid chips, since, given the small dimensions of the channels, they may clog the channels on the chip and hence destroy the operation of the chip, such as for example analyses based on the measuring of the fluid mixed with reagents to form some reaction corresponding to the measured quantity or parameter. This might for example be an optic reaction corresponding to the concentration of some substances in the fluid.

Fig. 4is a schematic a top view of a micro fluid chip (30) having two fluid inlets (31 , 32) for example being bores through the cover on a substrate, and making fluid communication from the externals to the two first fluid channels (33, 34) respectively, each of the two first fluid channels corresponding to a first conduit (4), and being connected to the two chambers (35, 36) corresponding to two first chambers (4), thus each having a gas permeable membrane (37, 38) covering the chambers (35, 36).

In each of the two first fluid channels (33, 34) is positioned a bubble generating pressure reduction unit (39, 40) that may in preferred embodiments optionally either be flow channels having substantially narrowed cross sectional areas compared to the rest of the flow channels in the micro fluidic chip, partial obstructions, a filter, small tubes, such as glass capillary tubes inserted into the channels (33, 34), etc. As seen, the micro fluid chip (30) shows an example of a degassing unit (2) comprising two parallel basic degassing units or systems (1).

Filters are positioned at the inlet faces of two second fluid channels corresponding to two second fluid conduits (20), as seen in Fig. 5 being a side view of the micro fluid chip (30). Fig. 5 shows one non-limiting example of a micro chip design of a plural of bodies, in the figure being three (50, 51 , 52), being stacked on top of each other. In the figure is seen one first fluid channel (33), the fluid inlet (31), the bubble generating pressure reduction unit (39) and the first chamber (35). The figure shows the first of the two basic degassing systems comprising a first channel (34) formed in the surface of the middle body (50), but it could also be made in the first cover body (51) or in both. The first chamber (35) is formed in the first cover body (51), but could alternatively be formed in the middle body (50) or both. The fluid inlet (31) is seen as a bore through the first cover body (51). The gas permeable membrane (37) is attached to the first cover body (51) forming one side wall of the first chamber (35). The filter (41) is squeezed between the two bodies (50, 51) and could optionally be positioned in a small cavity formed in one of the bodies or both. The bore (43) operates as the second fluid channel corresponding to a second fluid conduit (6), optionally having the small cavity (42). The bore (43) is in fluid connection with flow channels (45) optionally formed at the opposing surface of the middle body (50). The outlet of the flow channels (45) is seen as a bore (47). The second basic degassing system comprising the first fluid channel (34), fluid inlet (32), the bubble generating pressure reduction unit (40), the first chamber (36) etc., is preferably designed as a flow system comprising the first channel (34) as described above.

Returning to Fig. 4, the channel (45) is seen as a broken line indicating they are running along the surface of the body (50) opposite to the surface. The first channels (33, 34) are running along. The channels (45) comprise a meandering section and a meeting point (44) of branches, where fluids are mixed.

During operation fluids flowing into the system from the two fluid inlets (31 , 32) are flowing through the system to the meandering section (46) where some detector may be connected to measure effects of reactions occurring in the mixed fluids. One of the fluids may be a sample fluid being a fluid comprising substances of interest, the other fluid (or other fluids if more than two such basic degassing systems are present in the system) being a reagent to be mixed to the first fluid. The fluids are mixed according to Fick's laws about diffusion and a chemical reaction occurs depending on the properties of the fluid and the external conditions such as adding of energy to the system in the form of light (electromagnetic waves), heat, sound, etc.

The reaction(s) may form a chemical reaction giving, for example, an optic effect corresponding to some property or parameter like the concentration of a substance in one of (or all) the fluids. A detection of this may then occur somewhere between the mixer meander inlet and the mixer meander outlet, without any interference from bubbles. A pressure reduction unit (46) may be positioned between the outlet of the meandering section and the outlet (47) of the micro chip.

Fig. 6 is a schematic view of an analysis apparatus (101) according to a first more specific embodiment of the invention. The analysis apparatus (101) comprises a dosing reaction part (102) enclosing a fluid communication system (103) in the form of a number of pipes fluidly interconnecting various components of the analysis apparatus (101). The fluid communication system (103) is fluidly connected to a flow system in the form of a pipe (104), via a connector (105) inserted in the pipe (104). A filter (106) is arranged in the connector (105) in order to prevent impurities and unwanted particles from entering the analysis apparatus (101). A liquid (107) to be analysed flows in the pipe (104).

Inside the dosing reaction part (102) two reagent containers (108) and a mixing and reaction subsystem (109) are arranged. Each of the reagent containers (108) comprises a first volume (110a) containing reagent. The first volumes (110a) have flexible walls (110b), and each is arranged within a rigid wall of a respective reagent container (108) in such a manner that a second volume (110c) is defined between the first volume (110a) and the rigid walls. The second volume (110c) is fluidly connected to the fluid communication system (103). The pressure in the interior of the fluid communication system (103) is the same as the pressure of the liquid (107), P101. P101 is higher than an exterior pressure, P102, occurring outside the analysis apparatus (101).

The analysis apparatus (101) of Fig. 6 may preferably be operated in the following manner. Due to the pressure difference between P₁₀₁ and P₁₀₂, some liquid, in the following denoted sample fluid (111), is sucked from the pipe (104) into the fluid communication system (103) via the connector (105). Some of the sample fluid (111) flows into each of the second volumes (110c) of the reagent containers (108), via flow paths (112), the second volumes (110c) thereby adopting the pressure P₁₀₁- The pressure in the first volumes (110a) is P1₀2, as will be explained below, and consequently the flexible walls (110b) of the first volumes (110a) are squeezed, thereby causing reagent to flow from the first volumes (110a) towards the mixing and reaction subsystem (109) via flow paths (113) and flow restrictors (114). The flow rate of the reagent is determined by the pressure difference (P101-P102) and by the flow resistance of flow restrictors (113) in accordance with the formula .

Simultaneously, some of the sample fluid (111) flows via the fluid communication system and flow restrictor (115) into the mixing and reaction subsystem (109). The flow rate is determined by the pressure difference (P₁₀₁-P₁₀₂) and the flow resistance of the flow restrictor (115) in accordance with the formula

Fsample ⁼ (P 101 " P 102 ) / Rsample •

Accordingly, reagent and sample fluid (111) are mixed in the mixing and reaction subsystem (109), and chemical reactions between the reagent and the sample fluid (111) take place if specific soluble matter is present in the sample fluid (111). Since the flow rates of reagent and sample fluid (111) into the mixing and reaction subsystem (109) are all determined by the pressure difference, Pior Pio₂, the ratio of the flow rate of reagent and the flow rate of sample fluid (111) remains substantially constant, even in case of variations in the pressure difference or one or both of the pressures. Thereby it is ensured that the relative concentration of reagent and sample fluid (111) in the mixing and reaction subsystem (109) is substantially uniform, and very reliable measurements can thereby be obtained, without requiring pumps and complicated feedback mechanisms.

Finally, some of the sample fluid (111) flows directly into waste container (116), via flow restrictor (117), and further into sink (118) arranged outside the analysis apparatus (101). The sink (118) is provided with an opening (118a) providing communication between the sink (118) and the outside the analysis apparatus (101). Accordingly, the pressure inside the waste container (116) is the same as the external pressure, i.e. Pio2- Since the mixing and reaction subsystem (109) is fluidly connected to the waste container (116), the pressure inside the mixing and reaction subsystem (109) is also Pi_O2-

Still driven by the pressure difference, Pioi-Pio2, the mixed and reacted fluid flows into detection part (119). The detection part (119) generates a response signal in response to the reacted compounds present in the mixed and reacted fluid. Accordingly, the response signal is representative for the concentration of a specific soluble compound in the sample fluid (111), and thereby the concentration of this soluble compound in the liquid (107) flowing in the pipe (104).

A degassing unit (2) of any embodiment as described above, is positioned fluidic somewhere between the liquid (107) and outlet (118), preferably as part of, or at least fluidially connected to the fluid communication system (103) Fig. 7 is a schematic view of an analysis apparatus (101) according to a second, more specific embodiment of the invention. The parts of the embodiment shown in Fig. 6 are also present in the embodiment shown in Fig. 7, and they will therefore not be described in further detail here. The analysis apparatus (101) of Fig. 6 is further provided with a pressure reduction system used to reduce the pressure inside the fluid communication system (103) from the pressure. P_1Oi occurring in the pipe (104) to a working pressure, P_w. The pressure reduction system comprises a valve (120) arranged to fluidly connect the connector (105) and a reduction chamber (121) with a compliance chamber (122) having one or more flexible walls. The compliance chamber (122) contains air or a gas. A pressure transmitter (123) measures the pressure in the reduction chamber (121). An electronic circuit (124) controls the status of the valve (120), i.e. open or closed status, according to the pressure measured by the pressure transmitter (123). The pressure transmitter (123) and the valve (120) are connected to the electronic circuit (124) via electrical connections (125).

The pressure reduction system may preferably operate in the following manner. A working pressure, P_Wl is maintained in an interval between a lower set point value, P|_Ower, and an upper set point value, P_upPer- When the pressure in the reduction chamber (121), and thereby in the fluid communication system (103), reaches the lower set point value, Pi_0Wer, the control circuit (124) causes the valve (120) to open, and sample fluid (111) thereby flows into the reduction chamber (121) until the pressure in the reduction chamber (121) reaches the upper set point value, P_upper- At this point the control circuit (124) causes the valve (120) to close, thereby disrupting the flow of sample fluid (111). The discharge of the first volumes (110) of the reagent containers (108) results in a reduction of the pressure in the fluid communication system (103), and thereby in the reduction chamber (121), until the lower set point value, Piower, is once again reached, and the cycle described above is repeated. The compliance chamber (122) is embedded in the reduction chamber (121) in order to adjust the compliance of the reduction system to a value required for an optimal operation of the apparatus (101).

Again, a degassing unit (2) of any embodiment as described above, is positioned anywhere between the liquid (107) and the mixing and reaction subsystem (109), preferably as part of, or at least fluidly connected to the fluid communication system (103).

Fig. 8 further shows an example of an embodiment of an analysis apparatus of the present invention. The reagent section (150) is preferably is a combined pressurizing chamber (151) and reagent storage container(s) (152) system as described in the embodiments above (108, 110a, 11Ob₁ 110c), but other devices such as pressure regulation devices etc. could also be imagined, perhaps somehow regulating the pressures of the fluids in the analysis apparatus in relation to the pressure of the fluid to be analysed (107) and the external ambient (possibly atmospheric) pressure.

A first sample fluid conduit (154) of the second fluid conduit (6) (or the third, fourth, fifth etc. fluid conduit, if more than one basic (1) degassing unit or device is present in the analysis apparatus) connects it fluidly to the reagent section (150), more preferably to the pressurizing chamber (151).

A second section, the analysis section (155), comprises any structures and devices to analyse the content of the sample fluid (111) entering the system as a small part of fluid (107) and flowing to the analysis section (155) through a second sample fluid conduit (156) connecting the second fluid conduit (6) (or the third, fourth, fifth etc. fluid conduit, if more than one basic (1) degassing unit or device is present in the analysis apparatus) fluidly to the analysis section (155). The outlet (157) from the analysis section (155) is preferably connected to the externals having the ambient (possibly atmospheric) pressure. The analysis section (155) preferably corresponds to the dosing reaction part (102) of the above described embodiments of the present invention relating to Figs. 1-7, comprising any number and permutation of the parts described to those embodiments, such as, but not limited to, a fluid communication system (103), a mixing and reaction subsystem (109) etc.

The first and second sample fluid conduits (154, 156) preferable forms part of the fluid communication system (103) described in the embodiments above, but could alternatively be part of the degassing unit (2).

It could also optionally comprise such parts like the reagent containers (108) etc, but more preferably they form part of the reagent section (150).

A filter (160) is positioned somewhere in front of or in the second sample fluid conduit (156).

The second fluid conduit (6) preferably has an outlet (158) directly connected to the externals having the ambient (possibly atmospheric) pressure. A pressure reduction unit (159) is positioned between the inlet and the outlet of the second conduit (6), possibly extending out of the outlet.

The idea of this embodiment of the present invention is to ensure that the flow resistance through the flow path of the pressure reduction unit (159) is significantly lower than the flow resistance of the flow path through the filter (160), ensuring a significantly higher flow rate through the pressure reduction unit (159) compared to the filter (160), easily 10-1000 times higher, most preferably in the range of 50-200 times higher.

The advantage of this design is that any micro bubbles formed after the first chamber (4) will tend to take the path through the pressure reduction unit (159) rather than through the filter (160), thus being removed from the system rather than entering the critical parts of the system in the analysis section (155). One further major advantage is that the filter (160) filters the perfusion fluid for micro particles, and the fluid stream parallel to the filter running though the flow path of the pressure reduction unit (159) helps to clean the filter (160) to prevent clogging in time due to particles settling on the front side.

Optionally the analysis section (155) comprises degassing units (2) for some of or each fluid communication or conduit leading fluid(s) to the analysis section (155).

In one preferred, but not limiting, embodiment, the analysis section (155) is a micro fluid chip comprising channels for mixing (161) the sample fluid (111) to reagents arriving through reagent conduit(s) (163) from the reagent container(s) (152). As it is the case with the embodiments shown in Figs. 6 and 7, any number of reagents may be introduced into the system, and thus any number of reagent reservoirs or containers may be attached to the system, connected to the analysis apparatus through a corresponding number of reagent flow conduits. Further, the analysis section (155) comprises a (possibly meandering) channel section (162) possibly having a transparent cover, where an optic detector attached to the device measures optic effects of the mixed sample fluid (111) and reagents. Other kinds of detections, such as electrochemical etc. would also apply to the invention, the detector being of the relevant kind.

The analysis section (155) is shown comprising at least two degassing units (2) positioned before the critical mixing (161) of the fluids seen in the direction of flow in the system. One is in fluid connection with the second sample fluid conduit (156) and the other(s) is in fluid connection with the reagent fluid conduit(s) (163). The reagent section (150) could advantageously could be exchangeable for example in the manner that ink cartridges are exchanged in ink jet printers. In this manner the system may be operational for years, the reagents being exchanged when the reservoirs are, or are close to, being exhausted.

Preferably all outlets from the analysis apparatus, such as (157, 159)) end in some sink or reservoir (like (118)) collecting fluids leaving the system through the outlets, where the reservoir may be of a flexible material or may have for example a gas permeable but liquid impermeable wall section, to ensure the internal of the reservoir or sink has the pressure of the externals, the ambient (possibly atmospheric) pressure.

Claims

1. An analysis apparatus for analysing a fluid, the analysis apparatus comprising: - a fluid communication system arranged in an interior part of the analysis apparatus, said fluid communication system providing fluid communication between parts of the analysis apparatus,

- a detection unit adapted to receive and mix sample fluid and reagent, analyze said mixed fluid and generate output,

wherein, the analysis apparatus further comprises at least one basic degassing unit with a first fluid conduit having a first fluid inlet and a first fluid outlet, a first chamber in fluid connection with the first fluid outlet, and a first bubble generating and pressure reduction device at least partly situated between the first fluid inlet and the first chamber.

2. An analysis apparatus according to claim 1, wherein at least a part of the walls enclosing the first chamber is permeable to gas but impermeable to liquid.

3. An analysis apparatus according to claim 2, wherein the device further comprises a second fluid conduit having a second fluid inlet in fluid connection with the first chamber, and a second fluid outlet, wherein a filter is situated between the first chamber and the second fluid outlet.

4. An analysis apparatus according to claim 3, wherein the first bubble generating and pressure reduction unit extends into the first chamber.

5. An analysis apparatus according to claim 3, wherein a pressure reduction unit is situated between the second fluid inlet and the second fluid outlet, the pressure reduction unit.

6. An analysis apparatus according to claim 5, wherein the pressure reduction unit is bubble generating thus being a second bubble generating and pressure reduction unit.

7. An analysis apparatus according to claim 5, wherein the second fluid conduit is in fluid connection with the analysis section through a second sample fluid conduit, and where a filter is fluidly is connected to the second sample fluid conduit.

8. An analysis apparatus according to claim 7, wherein the second sample fluid conduit is in fluid connection with the second fluid conduit before the pressure reduction unit seen from the flow direction in the second fluid conduit, and where the second outlet of the second fluid conduit is connected to the externals.

9. An analysis apparatus according to claim 8, wherein the filter is attached in front of the inlet to the second sample fluid conduit.

10. An analysis apparatus according to any of the preceding claims, wherein the analysis apparatus comprises more than one basic degassing unit.

11. An analysis apparatus wherein the system comprises at least one degassing unit comprising any number and combination of basic degassing units according to any of the preceding claims, the basic degassing units being connected in series and/or in parallel.