WO2016003278A1

WO2016003278A1 - Combination of a cartridge for a microfluidic chip and a microfluidic chip

Info

Publication number: WO2016003278A1
Application number: PCT/NL2015/050481
Authority: WO
Inventors: Robin DE BRUIN
Original assignee: Emultech B.V.
Priority date: 2014-07-01
Filing date: 2015-06-30
Publication date: 2016-01-07
Also published as: NL1040873A; NL1040873B1

Abstract

The invention relates to Combination of a cartridge for a microfluidic chip and a microfluidic chip with at least two ports on a first side of the chip, which cartridge comprises: - a housing having a first housing part with a first chip contact surface arranged on a first side of the microfluidic chip and a second housing part with a second chip contact surface arranged on a second opposite side of the microfluidic chip; - a first sealing arranged between the first chip contact surface and the first side of the microfluidic chip; - a second sealing arranged between the second chip contact surface and the second side of the microfluidic chip; and - clamping means for clamping the microfluidic chip between the first and second housing parts; wherein the first housing part has a number of passage openings, each aligned with one of the at least two ports of the microfluidic chip; wherein the first sealing is a layer of sealing material, which layer comprises a number of passage openings, each aligned with one of the at least two ports of the microfluidic chip.

Description

Combination of a cartridge for a microfluidic chip and a microfluidic chip

The invention relates to a combination of a cartridge for a microfluidic chip and a microfluidic chip with at least two ports on a first side of the chip.

In the field of microfluidics fluids are moved, mixed, separated or otherwise processed, in which the

advantages of small volumes are used, such as laminar flows, low Reynold numbers and enhanced heat transfer. These fluids are fed from a fluid supply device to a microfluidic chip, which typically comprises a number of layers, such as glass layers and silicone layers, in which channels are etched. By appropriately designing the channels, complex processing of fluids can be achieved, such as for example the generation of monodisperse emulsions having complex particles, which could for example be used for drug delivery. The connection between the chip and the fluid supply device is typically performed by pressing fluid supply terminals ("connection terminals") of the device onto ports of the chip. A port is a location where a channel extends through the surface of the chip, and usually comprises a sealing to prevent leakage of fluid at the

connection .

The microfluidic chip is an expensive part, which needs to be handled carefully. To this end, such chips are typically arranged in a cartridge, which protects the chip from damage, while the cartridge enhances the handling. With a chip arranged in a cartridge it is easier to insert the chip in a device, such as a fluid supply device which supplies the fluids for the chip and which device drains the fluids processed by the chip.

Due to the small size of the microfluidic chip and of the ports to the internal channels, a high accuracy is required for the cartridge and for the connection terminals of the fluid supply device. If the connection terminals do not connect properly to the ports of the microfluidic chip, leakage can occur and undesired mixing of supply fluids and processed fluids can occur.

Especially, when the fluid pressures are relatively high, the connections between the cartridge and the chip are difficult to keep leak tight. If one would further tighten the cartridge around the microfluidic chip, it could damage the chip, or the chip would be deformed such that the microfluidic process inside the chip is affected.

Furthermore, the microfluidic chips need to be easily exchangeable from the cartridge in case a chip has broken down, for example due to clogging of one of the

channels .

US 2011044865 describes a cartridge for a microfluidic chip in which the chip is an elastic chip made of PDMS . It is positioned against a transparent bottom part of the cartridge, which is then closed by arranging a top part of the cartridge over the microfluidic chip. This top part is provided with an elastomer sealing, which seals the passage openings in the top part of the cartridge with the fluid supply lines to the ports on the microfluidic chip. The top part and bottom of the cartridge are then clamped together, with the microfluidic chip in between, by strong magnets, which also allows easy removal of the chip from the cartridge.

When non-aggressive fluids are processed by the chip, then a plurality of possible elastomer sealing materials is available to choose from. However, if aggressive fluids are to be processed, then the choices for a suitable sealing are substantially reduced. Typically sealing materials which are suitable for aggressive fluids are less elastic, which makes it difficult to provide a reliable sealing. Accordingly, it is an object of the invention to reduce or even remove the abovementioned disadvantages.

This object is achieved according to the invention with a combination of a cartridge for a microfluidic chip and a microfluidic chip with at least two ports on a first side of the chip, which cartridge comprises:

- a housing having a first housing part with a first chip contact surface arranged on a first side of the

microfluidic chip and a second housing part with a second chip contact surface arranged on a second opposite side of the microfluidic chip;

- a first sealing arranged between the first chip contact surface and the first side of the microfluidic chip;

- a second sealing arranged between the second chip contact surface and the second side of the microfluidic chip; and

- clamping means arranged along the periphery of the housing parts for clamping the microfluidic chip between the first and second housing parts,

wherein the first housing part has a number of passage openings, each aligned with one of the at least two ports of the microfluidic chip;

wherein the first sealing is a layer of sealing material, which layer comprises a number of passage openings, each aligned with one of the at least two ports of the

microfluidic chip.

With the combination according to the invention, the microfluidic chip is sandwiched between two sealings. The first sealing is selected based on the fluids to be processed by the microfluidic chip as this first sealing needs to seal the passage openings in the first housing part to the ports of the microfluidic chip.

The second sealing can be selected to provide more elasticity between the microfluidic chip and the cartridge, such that a clamping force of the clamping means can be distributed more evenly over the microfluidic chip. This enables one to increase the clamping force, compared to prior art solutions, without damaging the chip. Especially, when the first sealing has a relative low elasticity or a relative high hardness, due to the requirements as a result of the fluid to be processed, the increased clamping force allows higher fluid pressures to be applied compared to prior art solutions. This also enables one to reduce costs, as it is no longer necessary that a single sealing fulfills all requirements, such as elasticity and resistance to the fluids to be processed.

In a preferred embodiment of the combination of the invention, the first sealing has a higher hardness than the second sealing. For example, the hardness of the first sealing is Shore 75A or more and the hardness of the second sealing is Shore 70A or less. In another example, the hardness of the first sealing is Shore 80A or more and the hardness of the second sealing is Shore 70A or less. In yet another example, the hardness of the first sealing is Shore 80A or more and the hardness of the second sealing is Shore 75A or less.

In particular, the first sealing has a higher elastic modulus than the second sealing, more in particular it has a higher Young's modulus. In principle, any Young's modulus can be chosen for the first sealing, as long as it is higher than that of the second sealing. Usually, however, the Young's modulus of the first sealing is 1 MPa or more, 2 MPa or more, 3 MPa or more, 5 MPa or more, 10 MPa or more, 15 MPa or more, 20 MPa or more, 50 MPa or more, 100 MPa or more, 200 MPa or more, 300 MPa or more, 400 MPa or more, or 500 MPa or more. The Young's modulus of the second sealing is usually 500 MPa or less, 400 MPa or less, 300 MPa or less, 200 MPa or less, 100 MPa or less, 50 MPa or less, 20 MPa or less, 15 MPa or less, 10 MPa or less, 5 MPa or less, 3 MPa or less, 2 MPa or less, or 1 MPa or less. For example, the Young's modulus of the first sealing is 25 MPa or more and the Young's modulus of the second sealing is 10 MPa or less. In another example, the Young's modulus of the first sealing is 20 MPa or more and the Young's modulus of the second sealing is 15 MPa or less. In yet another example, the Young's modulus of the first sealing is 40 MPa or more and the Young's modulus of the second sealing is 10 MPa or less.

In an embodiment, the first sealing comprises a material selected from the group of polyimides, rubbers, polycarbonates, polyesters, polyethers, polyurethanes , polyacrylates , polymethylmethacrylate, polyolefins,

fluorinated polyolefins, mixtures of fluorinated polyolefins, polyethylene, polyethylene terephthalate, polypropylene, polystyrene, polyvinylchloride, polyamides, polystyrene, polyethyleneglycol , polypropyleneglycol and

poly (paraphenylenesulfide) .

In a further preferred embodiment of the combination according to the invention, the first sealing consists of a chemical-resistant material. A chemical-resistant material is a material that has a high effectiveness against chemical degradation. It often acts as a protective material against a particular chemical. A chemical-resistant material is

considered to be only marginally affected by physical contact with such chemical, in other words it is compatible with it. Usually, chemical resistance is associated with chemicals that are considered aggressive or corrosive, for example oxidising substances, strong acids or bases, or aggressive solvents. A person skilled in the art knows which kind of (protective) material can be used in order to reach compatibility with a particular chemical.

In particular, the first sealing consists of a fluorinated polymer or of a mixture of fluorinated polymers. A fluorinated polymer is in particular a fluorinated polyolefin such as polytetrafluoroethylene (PTFE) . In a preferred

embodiment, the first sealing consists of expanded PTFE.

A preferred embodiment of expanded PTFE is for example sold under the tradename Soft-Chem by Klinger GmbH having preferably a hardness of Shore 75A.

Expanded PTFE is very suitable for aggressive fluids and still has sufficient elasticity, such that the expanded PTFE can be used as a sealing.

In yet another embodiment of the combination

according to the invention the second sealing consists of an elastic material, preferably an elastomer, in particular a fluorinated elastomer. More preferably, the second sealing consists of a mixture of fluorinated elastomers, or a mixture of perfluorinated elastomers or a mixture of

tetrafluoroethylene/propylene rubbers. In particular, it consists of vinylidene fluoride-based elastomer such as poly ( vinylidenefluoride) (PVDF) . A preferred embodiment of a mixture of fluorinated elastomers is for example sold under tradename Viton by DuPont Performance Elastomers L.L.C.

Such a mixture of fluorinated elastomers has a high elasticity or low hardness, such that it is very suitable for a compressible sealing. It has the further advantage, that the material has a high resistance to solvents, acids and bases, which are typically used in microfluidic chips.

In another embodiment, the second sealing comprises an elastomer, in particular an elastomer selected from the group of polyisoprenes , polybutadienes , chloroprene rubbers, butyl rubbers, halogenated butyl rubbers, styrene-butadiene rubbers, nitrile rubbers, ethylene propylene rubbers, ethylene propylene diene rubbers, epichlorohydrin rubbers, polyacrylic rubbers, silicone rubbers, fluorosilicone rubbers, fluoroelastomers , fluorinated elastomers, perfluoroelastomers, polyether block amides, chlorosulfonated polyethylene, and ethylene-vinyl acetate.

In another embodiment of the combination according to the invention, the first sealing consists of a material selected from the group of epoxy resins, polyvinyl chloride, polyethylene, polypropylene and polyamides.

In a combination according to the invention, the first sealing (and optionally also the second sealing) is a layer of sealing material. The layer comprises a number of passage openings, each of which is aligned with one of the at least two ports of the microfluidic chip. By using a layer of sealing material, the respective chip contact surface can be lined with this sealing layer, without the need to exactly position the sealing around each of the ports of the

microfluidic chip, as is usually the case when a plurality of separate 0-rings are used. Since the passage openings in the first sealing have a fixed relative position, the only

required positioning is that of the entire first sealing, by which all passage openings are brought in line with the ports at once .

The layer of sealing may cover the entire chip contact surface or part of it. Usually, it covers at least 50% of the surface. It may also cover at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the surface.

The housing parts of the cartridge are usually made from a material that is rigid, i.e. a material that does not deform substantially under the pressure applied to it during normal operation of the combination of the invention. The elastic modulus (Young's modulus) of such material is for example 10 GPa or higher, 5 GPa or higher, 2 GPa or higher, 1 GPa or higher, 700 MPa or higher, 500 MPa or higher, 400 MPa or higher, 300 MPa or higher, 200 MPa or higher, or 100 MPa or higher. A cartridge is for example made of a material selected from the group of ceramic materials (such as glass), metals (such as steel) or polymers (for example cyclic olefin

copolymer) .

If the material of the housing would substantially deform when placed in the fluid supply device and/or when the clamping means exert a force that presses together both housing parts, then the tight fit of the first sealing around the ports in the combination of the invention may be disrupted which may lead to leakage when the chip is operational in a device .

In addition, the chip itself is preferably also designed as a rigid entity. This means that the chip

preferably does not substantially deform under the pressure applied to it during normal operation of the combination of the invention. Otherwise, its channels may deform and/or leakage may occur when the chip is operational in a device. The elastic modulus (Young's modulus) of such material is for example 10 GPa or higher, 5 GPa or hogher, 2 GPa or higher, 1 GPa or higher, 700 MPa or higher, 500 MPa or higher, 400 MPa or higher, 300 MPa or higher, 200 MPa or higher, or 100 MPa or higher. The chip for example comprises a material selected from the group of ceramic materials (such as glass), metals (such as steel) and polymers.

It has surprisingly been found that with a combination of the invention it is possible to create a connection with a fluid supply device, wherein the connection can withstand pressures that are substantially higher than the pressures that can be withstood by connections between such device and a conventional chip. Thus, the present invention allows to make a microfluidic reaction set-up (i.e. an

operational apparatus for a microfluidic reaction) that can operate at higher pressures than conventional microfluidic reaction set-ups. The pressures that can be handled without any leakage can be up to and including 5 bars, up to and including 6 bars, up to and including 8 bars, up to and including 10 bars, up to and including 12 bars, up to and including 15 bars, up to and including 20 bars, or even up to and including 25 bars.

An example of a combination of the invention

comprises the features:

1) a first and a second housing part made of cyclic olefin copolymer, clamped together around a chip by metal screws in their periphery;

2) a chip with five ports on the same side, comprising a layer of silicon wherein channels are etched, which layer is sandwiched between two layers of borosilicate glass;

3) a first sealing of expanded PTFE comprising five passage holes of 1 mm cross-section, which passage openings are aligned with the ports;

4) a second sealing of Viton® fluoropolymer elastomer;

5) five passage holes of 5 mm cross-section in the first housing part, which passage holes are aligned with the ports .

With this particular combination, a connection of a fluid supply device with each of the five ports was made, wherein each connection was leak-tight at a pressure of up to 15 bars.

Typically, conventional chips with comparable functionalities operate at approximately three bars, having 5 bars as the ultimate operating pressure. This demonstrates the highly improved properties of a combination of the invention.

Thus, the invention is in particular suitable for applications wherein high pressures (e.g. of up to 10, 12, 15 or 20 bars) are used. This does not only account for the microfluidic processes that are intended to be carried out, but also for processes associated with maintenance of the microfluidic chip. Since high pressures can be used, flushing of the chip while in the device (for e.g. cleaning or

unclogging) is more effective than in devices that comprise conventional chips that only can resist substantially lower pressures. Whereas conventional chips would require

replacement in such cases (or at least a temporary removal from the fluid supply device for cleaning in another device), a combination of the invention can be made operational again without removing it from the device. Since maintenance can (in some or all cases) be performed without disconnection from the fluid supply device, a combination of the invention will undergo less events of disconnection and reconnection during its lifetime. This has the additional effect that the downtime of the entire microfluidic set-up (i.e. the apparatus for carrying out microfluidic processes) is decreased.

Ultimately, a combination of the invention can be in its place during its entire lifetime, i.e. it is only

connected once during its entire lifetime. When this would be the true intention of using a combination of the invention in a fluid supply device, then the requirements the first sealing would have to comply with can be less stringent. This in particular applies to the capability of the sealing to repeatedly realize a leak-tight connection with the device. A sealing that can only create a leak-tight connection at the first time it is connected to a connection terminal, would then suffice. In this way, the use of sealings with a lower elasticity than sealings of conventional chips comes into reach, in particular sealings that deform permanently due to the connection with a connection terminal, and/or sealings that upon second connection do fit less tightly around a connection terminal. A material that appeared in particular suitable for a once-only connection, is expanded PTFE .

Moreover, this material exhibits a high chemical resistance, which expands the scope of application of the combination comprising such sealing.

Other materials that advantageously come into reach of application in a microfluidic chip are those that are approved by the different national authorities who decide on whether materials may be used in food and medicine, such as FDA and EMA.

A combination of the present invention is in

particular suitable for microfluidic chips that have a complex topography and more than two ports. For example, the

microfluidic chip has three or more ports, four or more ports, five or more ports, six or more ports, seven or more ports or eight or more ports. The number of passage openings in the first sealing and in the first housing is then (at least) equal to the number of ports.

In the art, it appears that the leak-tightness of the connections with the chips decreases strongly with an increasing number of ports. This is because the design of such chips makes it difficult to create a proper connection of all the ports at the same time, even after time-consuming efforts to adjust the position of the relevant elements in the set-up and the eventual pressures that are present between them. Due to the special design of the combination of the invention, it is possible to achieve a leak-tight connection of connection terminals at three or more ports at the same time, which connections are capable of withstanding high pressures.

In an embodiment, the clamping means press together the first housing part and the second housing part with a particular force. This means that the clamping means not only hold together both housing parts, but also press them together so that at least one of the seals is substantially compressed and thereby deformed. For the purpose of the present

invention, the pressure resulting from such force will be termed "pretension", and the application such pressure will be termed "pretensioning" .

The pretension is for example in the range of 1- 10,000 kPa, in particular in the range of 10-1,000 kPa. It may be at least 1 kPa, at least 10 kPa, at least 50 kPa, at least 100 kPa, at least 200 kPa, at least 500 kPa, at least 1,000 kPa, at least 2,000 kPa, at least 5,000 kPa, at least 10,000 kPa, at least 20,000 kPa, at least 50,000 kPa or at least 100,000 kPa. It may be 100,000 kPa or less, 50,000 kPa or less, 20,000 kPa or less, 10,000 kPa or less, 5,000 kPa or less, 2,000 kPa or less, 1,000 kPa or less, 500 kPa or less or 100 kPa or less.

In an embodiment, the clamping means are threaded fasteners protruding through both housing parts, for example bolts on which a nut is screwed. In an embodiment, a

combination of the invention comprises a plurality of such fasteners, located around the periphery of the housing.

Usually, their number is in the range of 4-10, for example eight. By tightening the nuts, the pretension can be created and adjusted to a certain level.

An advantage of the pretension in the cartridge appeared to be that the connections between the combination of the invention and the fluid supply device can withstand pressures that are significantly higher than those that can be withstood by connections between such device and a

conventional chip.

In yet another preferred embodiment of the combination according to the invention pressure increasing means are arranged around the ports of the microfluidic chip. If despite the fact that the microfluidic chip is sandwiched between two sealings, the fluid pressure is too high to ensure a sufficient sealing around the ports of the chip, one could provide pressure increasing means, to locally increase the pressure around the ports onto the sealing such that the required leak tightness is achieved.

Preferably, the pressure increasing means comprise ridges either arranged around the openings in the first sealing or arranged around the passage openings in the first housing parts.

These ridges ensure that the first sealing is locally, around the ports, further compressed (i.e. at such locations the pressure on the seal is increased) such that the sealing can withstand higher fluid pressures inside of the ports. The ridges also provide means for centering the

microfluidic chip relative to the sealing and the cartridge housing. The microfluidic chip could even be provided with a shallow groove around the ports, such that the ridges can be accommodated in these shallow grooves and centering is ensured .

In another embodiment of the combination according to the invention the pressure increasing means comprise enlarged passage openings in the first housing part for passage of connection terminals and for direct contact between the tip of the connection terminals with the first sealing.

Instead of providing ridges in the cartridge to locally increase the sealing pressure, one could also have the connection terminals of the device, in which a cartridge is positioned, to extend through the passage openings in the first housing part and be in direct contact with the first sealing.

The cartridge will still protect the microfluidic chip from damage as the housing will still fully enclose the chip. By designing the fluid supply device such that the connection terminals extend slightly further from the device, than the thickness of the first housing part, it is ensured that after positioning the cartridge in the device, the connection terminals extend through the first housing part and are pressed against the first sealing. The second sealing will still provide additional flexibility between the chip and the cartridge to ensure that the connection terminals do not damage the chip.

When placed in a fluid supply device, a combination of the invention is usually hold and kept in position by placing preferably only the second housing part into a holder of the device. The connection terminals can then extend through the passage openings of the first housing part without touching it. The connection terminals would then touch the first sealing and thereby realize the connection between the fluid supply device and a combination of the invention. In principle, it is not necessary that any part of the fluid supply device is attached to or even touches the first housing part. In this way, a force by which both housing parts are pressed together cannot be subject to variations as a result of the placement of the combination of the chip and the cartridge in the fluid supply device (and if no force is present, there is no creation of a force that presses both housing parts together) . A combination of the invention is designed to be placed in a fluid supply device in this manner.

Accordingly, the invention further relates to an apparatus comprising a fluid supply device and a combination of the invention, wherein the fluid supply device comprises a holder that keeps the combination into a position, wherein the holder only holds the second housing part and wherein the device exerts essentially no pressure on the first housing part. The fluid supply device is also capable of receiving one or more fluids, such as drain fluids exiting the microfluidic chip .

In a particular method of making such apparatus and getting it in an operational condition, the placement of a combination of the invention in a fluid supply device would essentially only require 1) placing the second housing in the holder; 2) guiding the connection terminals through the passage openings in the first housing part that are aligned with the ports that are to be connected; and 3) pressing the connection terminals on the first sealing that is arranged around these ports.

The force with which the connection terminals are pressed on the first sealing typically depends on the number of connection terminals, the type of sealing, the thickness of the sealing, the size and shape of the ports (in particular their cross-section) , the size and shape of the passage openings in the sealing (in particular their cross-section), the size and shape of the passage openings in the first housing part at the interface of the first housing part and the first sealing (in particular their cross-section), and the size and shape of the connection terminals (in particular their cross-section) . A person skilled in the art will be able to choose an appropriate pressure taking into account these factors by routine experimentation and without exerting inventive effort.

In view of the preference to hold only the second housing part, it is advantageous that all ports to be

connected are present at the same side of the combination, namely at the side of the first housing part. If ports to be connected would be present on either side, then pressure would be exerted on both sides of the combination, which would likely require more finetuning in positioning and application of pressure in order get all connections in order. Thus, in a preferred embodiment, a combination of the invention has all its ports on the same side of the chip (and thus of the combination) , which is typically on the side of the first housing part .

An advantage of holding only the second housing part (and not holding the first housing part, or exerting pressure thereto) and of having all ports on the side of the first housing part, is that the placement of the combination in the fluid supply device is convenient and that a leak free

connection of the device with the combination of the invention can be obtained in one step without further adjusting the position of other elements of the device and/or the

combination, and/or without adjusting the pressure exerted to such elements, in order to reach a leak-free connection. It appeared that the more ports that are to be leak-free

connected, the higher is the advantage when a combination of the invention is used. This is because in conventional

microfluidic chips, the connection of an increased amount of ports is associated with a severely increased chance on leakage of one of the connections.

Another advantage of this particular design of the combination of the invention and the abovedescribed mode of placement in a fluid supply device is that the connections between the combination and the device can withstand pressures that are substantially higher than the pressures that can be withstood by connections between such device and a

conventional chip.

Thus, two forces are of importance when applying a combination of the invention: 1) the force of the

pretensioning and 2) the force with which the connection terminals are pressed on the first sealing. Both forces act independently from each other, which has the advantage that the positioning of the combination in a device is convenient while at the same time the connections are leak-tight. This allows a fast replacement (since there are no time-consuming adjustments) as well as an effective replacement (because of the resulting leak-tight connections) of a microfluidic chip in a fluid supply device and so deceases the down time of the entire apparatus.

The passage openings in the first housing may have the same shape and size as the passage openings in the first sealing. Preferably, however, they are larger than the passage openings in the first sealing. This is preferred because when the passage openings in the sealing are smaller than those in the housing, the connection terminals can extend through the latter without touching the housing, and can then touch the sealing, press on it, and eventually penetrate it through the passage openings therein. The parts of the sealing that are not covered by the first housing part (i.e. those parts of the sealing that are visible through the passage openings in the first housing part) can then deform due to the pressing of the connection terminals and accommodate for the eventual

insertion of the connection terminals through the first sealing into the ports when the connection terminals have a larger opening than the passage openings in the sealing. The extent to which the passage openings in the first sealing are smaller than those in the first housing part may depend on several factors, such as the type of sealing material, the thickness of the sealing material, how the size of the passage openings in the first sealing relates to the size of the connection terminals (in particular to their cross-section), and how the size of the passage openings in the first sealing relates to the size of the ports (in particular to their cross-section) . A person skilled in the art will be able to choose the appropriate dimensions of the passage openings (in the first housing part as well as in the first sealing) , the ports and the connection terminals, by routine experimentation and without exerting inventive effort.

Generally speaking, however, the largest dimension of the passage openings (or the cross-section of the passage openings) in the first housing part is 1.2-10 times larger than the largest dimension of the passage openings (or the cross-section of the passage openings) in the first sealing. In particular, it is 1.5-9.0 times larger, 2.0-8.0 times larger, 2.5-7.0 times larger or 3.0-6.0 times larger.

A combination of the invention may contain a microfluidic chip in a variety of sizes. Usually, however, the chip is dimensioned such that its longest cross-section in the plane of the first and the second chip contact surface is in the range of 5-500 mm, in particular in the range of 10-100 mm .

The passage openings in the first sealing may also have different dimensions, depending on e.g. the type of sealing material, the thickness of the sealing material, how the size of the passage openings in the first sealing relates to the size of the connection terminals (in particular to their cross-section), how the size of the passage openings in the first sealing relates to the size of the ports (in

particular to their cross-section) , and how the size of the passage openings in the first sealing relates to the size of the ports (in particular to their cross-section) . Usually, the longest cross-section of the passage openings in the first sealing is in the range of 0.005-20 mm, in particular in the range of 0.01-12.0 mm, in the range of 0.02-8.0 mm, in the range of 0.05-6.0 mm, or in the range of 0.1-4.0 mm.

The cross-section of the ports is usually larger than that of the passage openings in the first sealing. This results in a leak-tight connection when a connection terminal is connected to the port. The cross-section of the ports is usually 1.05-2.5 times larger, preferably it is 1.1-2.0 times larger .

It was thus found that several features contributed to the leak-tightness of a combination of the invention.

Specifically, a combination of the invention that was designed to be placed in the device only by holding the second housing part (and not the first) and that comprises 1) a continuous seal; 2) a pretension; 3) a first sealing with a higher

Young's modulus than a second sealing; and 4) pressure

increasing means such as ridges; appeared to be capable of handling the highest pressures during operation, e.g. of up to 20 bars .

In yet a further embodiment of the combination according to the invention a channel of the microfluidic chip is composed out of a groove in the second side of the

microfluidic chip and the second sealing.

As the microfluidic chip is clamped into the

cartridge, the chip would not need a cover layer to close off all channels. The housing parts of the cartridge can

contribute to the microfluidic chip, especially as the chip is sandwiched between two sealings. Because the sealings

typically are resistant to the fluids used in the microfluidic chip, the sealings can also be part of a channel in the chip.

In still a further embodiment of the combination according to the invention the microfluidic chip comprises two ports on the second side and a bypass channel is arranged in the second housing part for connecting the two ports on the second side.

Due to the availability of the second sealing, it is also possible to incorporate parts of the functionality of the microfluidic chip into the second housing part.

These and other features of the invention will be elucidated in conjunction with the accompanying drawings.

Figure 1 shows a cross sectional view of a first embodiment of the combination according to the invention.

Figure 2 shows a cross sectional view of a second embodiment of the combination according to the invention.

Figure 3 shows an enlarged cross sectional portion of a third embodiment of the combination according to the invention .

Figure 4 shows an enlarged cross sectional portion of a fourth embodiment of the combination according to the invention .

Figure 5 shows a cross sectional view of a fifth embodiment of the combination according to the invention.

Figure 6 shows a cross sectional view of a sixth embodiment of the combination according to the invention.

Figure 1 shows a cross sectional view of a first embodiment 1 of the combination according to the invention.

The embodiment 1 has a cartridge with a first housing part 2 and a second housing part 3. The first housing part 2 has a first chip contact surface 4 and the second housing part 3 has a second chip contact surface 5.

A first sealing layer 6 is arranged to the first chip contact surface 4, while a second sealing layer 7 is arranged to the second chip contact surface 5.

A microfluidic chip 8 is arranged between these two sealing layers 6, 7. The microfluidic chip 8 is composed out of a number of etched layers, such that in this example a first channel 9 with a port 10 and a second channel 11 with ports 12, 13 is formed. The first sealing layer 6 is provided with openings corresponding to the ports 10, 12, 13.

Also, the first housing part 2 has passage openings 14, 15, 16 corresponding to the ports 10, 12, 13 respectively.

The housing parts 2, 3 are clamped together by bolts 17, 18 such that the microfluidic chip 8 is sandwiched between the housing parts 2, 3 and the sealings 6, 7. Because the first sealing layer 6 is in contact with the fluid in the first channel 9 and the second channel 11 of the microfluidic chip 8, the sealing material of this sealing 6 has to comply to certain requirements. On the other hand, the second sealing 7 will not be in contact with fluid and can be optimized for flexibility, such that the clamping force of the housing 2, 3 is distributed evenly over the chip 8 and a leak tight sealing is obtained between the ports 10, 12, 13 and the first housing part 2.

Figure 2 shows a cross sectional view of a second embodiment 20 of the combination according to the invention. Parts similar to the parts of the first embodiment shown in figure 1 have the same reference signs.

The first housing part 2 has in this embodiment enlarged passage openings 21, 22, 23, through which connection terminals 24, 25, 26 of a device for supplying fluid and discharging fluid extend and are pushed into contact with the first sealing 6. The second sealing 7 provides additional flexibility, such that the microfluidic chip 8 can be pressed upwardly inside of the cartridge 2, 3 in case the contact pressure of the connection terminals 24, 25, 26 would be too high .

Figure 3 shows an enlarged cross sectional portion of a third embodiment 30 of the combination according to the invention. This embodiment 30, which is similar to the

embodiment 1, has a ridge 31 arranged on the first housing part 2 around the passage opening 15. When the housing parts 2, 3 are clamped together, this ridge 31 will provide a local pressure increase on the first sealing 6, such that an

improved sealing is provided of the port 12 of the chip 8 onto the first housing part 2.

Figure 4 shows an enlarged cross sectional portion of a fourth embodiment 40 of the combination according to the invention. In this embodiment 40, the first sealing 6 is provided with a ridge 41, such that an increased pressure is obtained when all the parts of the combination 40 are clamped together. To further assist in centering the chip 8 relative to the sealing 6, the chip 8 is provided with a groove 42 around the port 12, such that the ridge 41 can engage in the groove 42.

Figure 5 shows a cross sectional view of a fifth embodiment 50 of the combination according to the invention. In this embodiment 50, the channel 51 provided in the chip 8 runs partially along the top surface of the chip 8. Because a second sealing 7 is provided to the second chip contact surface 5 of the second housing part 3, this channel part 51 will still be fluid tight. So, due to the second sealing 7, the construction of the chip can be simplified, as the sealing 7 provides for a closing layer of the chip 8.

Figure 6 shows a cross sectional view of a sixth embodiment 60 of the combination according to the invention. In this embodiment 60 the second housing part 3 is provided with a bypass channel 61 and the second sealing 7 is provided with openings 62, 63 which correspond to the ports 64, 65 respectively arranged in the top surface of the chip 8. Due to the second sealing layer 7 a leak tight connection of the ports 64, 65 to the bypass channel 61 is provided, while the ports 10, 12, 13 arranged on the bottom surface of the chip 8 are also leak tight connected to the first housing part 2.

Claims

1. Combination of a cartridge for a microfluidic chip and a microfluidic chip with at least two ports on a first side of the chip, which cartridge comprises:

- clamping means for clamping the microfluidic chip between the first and second housing parts;

microfluidic chip.

2. Combination according to claim 1, wherein the first sealing has a higher elastic modulus and/or a higher hardness than the second sealing.

3. Combination according to claim 1 or 2, wherein the Young's modulus of the first sealing is 20 MPa or more and the Young's modulus of the second sealing is 15 MPa or less.

4. Combination according to claim 1 or 2, wherein the hardness of the first sealing is Shore 75A or more and the hardness of the second sealing is Shore 70A or less.

5. Combination according to any of the preceding claims, wherein the first sealing comprises a material

selected from the group of polyimides, rubbers,

polycarbonates, polyesters, polyethers, polyurethanes ,

polyacrylates , polymethylmethacrylate, polyolefins,

poly (paraphenylenesulfide) .

6. Combination according to any of the preceding claims, wherein the first sealing comprises

polytetrafluoroethylene (PTFE) , in particular expanded

polytetrafluoroethylene (EPTFE) .

7. Combination according to any of the preceding claims, wherein the second sealing comprises an elastomer, in particular an elastomer selected from the group of

polyisoprenes , polybutadienes , chloroprene rubbers, butyl rubbers, halogenated butyl rubbers, styrene-butadiene rubbers, nitrile rubbers, ethylene propylene rubbers, ethylene

propylene diene rubbers, epichlorohydrin rubbers, polyacrylic rubbers, silicone rubbers, fluorosilicone rubbers,

fluoroelastomers , fluorinated elastomers, perfluoroelastomers, polyether block amides, chlorosulfonated polyethylene, and ethylene-vinyl acetate.

8. Combination according to any of the preceding claims, wherein the cross-section of the passage openings in the first housing part is 1.2-10 times larger than the cross- section of the passage openings in the first sealing, in particular it is 3.0-6.0 times larger.

9. Combination according to any of the preceding claims, wherein the longest cross-section in the plane of the first and the second chip contact surface is in the range of 5-500 mm, in particular in the range of 10-100 mm.

10. Combination according to any of the preceding claims, wherein the cross-section of the passage openings in the first sealing is in the range of 0.005-20 mm, in

particular in the range of 0.1-4.0 mm.

11. Combination according to any of the preceding claims, wherein the clamping means press together the first housing part and the second housing part with a force in the range of 1-10,000 kPa, in particular in the range of 10- 1,000 kPa.

12. Combination according to any of the preceding claims, wherein the microfluidic chip has three or more ports.

13. Combination according to any of the preceding claims, wherein pressure increasing means are arranged around the ports of the microfluidic chip, which means comprise ridges either arranged around the openings in the first sealing or arranged around the passage openings in the first housing parts.

14. Combination according to any of the preceding claims, wherein the pressure increasing means comprise

enlarged passage openings in the first housing part for passage of connection terminals and for direct contact between the tip of the connection terminals with the first sealing.

15. Combination according to any of the preceding claims, wherein a channel of the microfluidic chip is composed out of a groove in the second side of the microfluidic chip and the second sealing.