The present invention relates to a micro-fluidic system comprising: a. a planar micro-fluidic device comprising a plurality of inlets and at least one out-let; b. a holder comprising a first part being provided with a plurality of channels having first ends and second ends, the holder comprising a fixing means for clamping the micro-fluidic device; c. sealing means being arranged to connect the plurality of inlets and the at least one out-let of the micro-fluidic device to the second ends of the plurality of channels, the sealing means being arranged such that a surface contact between the micro- fluidic device and the sealing means and a surface contact between the sealing means and the first part of the holder is established.

Micro-fluidic systems are defined as having at least one dimension in the sub-millimeter region. The word 'fluidic' is, in the context of the present invention construed as 'involving liquid and/or gaseous components'.

In WO2004/022233 a modular micro-fluidic system has been described having at least one base board with a plurality of fluidly linked fluid supply apertures, optional intermediate level boards of equivalent construction, a plurality of micro-fluidic modules adapted to be detachably attached to the base board/ intermediate boards, each having one or more fluid inlets and/or outlets, and a plurality of fluid connections. Conveniently, the connections comprise releasable couplings, for example in the form of a channel means removably insertable into a suitable recess in such an inlet/outlet/aperture to effect a fluid tight communicating connection there between. Such a channel means conveniently comprises a tubular element, in particular a rigid tubular element, for example being parallel sided, for example being square or rectangular, polygonal, or alternatively having a circular or elliptical cross section, with any recess into which such a tubular element is to be received preferably being shaped accordingly. Such a tubular element can be a separable and distinct unit. However, the tubular element preferably comprises a projecting ferrule integral with and projecting from a first aperture comprising either a fluid supply aperture in the base board or an inlet/outlet in the module, and adapted to be received in a recess comprised as a second aperture, correspondingly either an inlet/outlet in the module or a supply aperture in the base board. In particular the ferrule projects generally perpendicularly from a generally planar surface, to effect a fluid connection between a base board and module adapted to lie generally parallel when connected.

In a most preferred form, ferrules are provided which project above the surface of the base board to be received within recesses comprising the inlet/outlet apertures of modules to be attached thereto. The ferrule system enables dead volume in fluid path between "chips" to be minimized. Use of ferrules allows higher density of interconnections than other fittings such as high- pressure liquid chromatography (HPLC) fittings and the like.

Ferrules can withstand high pressures. The ferrules ensure accurate mechanical alignment of fluid elements making accurate module placement easy.

A disadvantage of such ferrule systems is that when a micro-fluidic system comprising such ferrule interconnections is operated at elevated pressures in combination with high temperatures, the ferrules will thermally expand. This thermal expansion is spatially restricted due to the tight fitting of the ferrules inside the recesses in the reactor chip and in the base or intermediate board. Therefore, the ferrules are deformed outside the elastic region of the material (plastic deformation), especially when the ferrules are of a rigid material. Such a plastic deformation of the ferrule material permanently changes the mechanical properties of the ferrule material, which therefore loses its sealing capability and the micro-fluidic system starts to leak. Another disadvantage of the micro-fluidic systems described in WO2004/022233 is that although the ferrules ensure accurate mechanical alignment of fluid elements, such element, which are for example the micro-reactor chip and the base board, need to be manufactured with very high alignment accuracy, i.e. the positions and sizes of the counteracting recesses in both the micro-reactor chip and the base board need to be very accurately tuned, in particular when a large number of connections have to be established.

It is an object of the present invention to provide a micro-fluidic system that can be operated at a high pressures (up to 80 bar) in combination with high a temperature (up to 200 ⁰ C) and for which system at least part of the above disadvantages are absent or at least mitigated.

This object has been achieved by a micro-fluidic system according to the preamble, characterized in that the first part of the holder is optionally provided with a first recess for accommodating the planar micro-fluidic device, the second ends of the plurality of channels being located within the optional first recess and at least one second recess is provided for accommodating the sealing means, the second ends of the plurality of channels being located in the at least one second recess.. The at least one second recess is therefore located within the first recess for accommodating the sealing means. The micro-fluidic device is clamped in the holder such that the sealing means deform within the elastic region of the material which compares to, dependent on the selected sealing material, uniaxial compression of the sealing means and hence reducing its thickness between 5%-40%, preferably between 10%-30%, more preferably between 15%-25%. In this way a fluid tight connection is established that can withstand high pressures. Heating the micro-fluidic system to said temperatures, the sealing means may thermally expand without being restricted by tight recesses wherein the sealing means is fitted, the absence of such thus preventing additional mechanical stresses caused by spatially restricted thermal expansion of the sealing means. The deformation of the sealing means therefore remains within the elastic region of the sealing material. Permanent changes of the mechanical properties of the sealing material due to plastic deformation are omitted or at least mitigated. Therefore the sealing means retains its sealing properties over a longer period of time and contributes to a substantially leak-free micro-fluidic system. To secure that the compression of the sealing means remains within the above stated ranges, in order to avoid plastic deformation of the sealing means, the depth of the at least one second recess (d ₂ ) may be between 60% and 95%, preferably between 70% and 90%, more preferably between 75% and 85% of the pre-compression thickness of the sealing means (t ₂ ). The pre-compression thickness of the sealing means is to be understood to be the thickness of the sealing means prior to placement in the micro-fluidic system and therefore prior to compressive loading of the sealing means. The second ends of the plurality of the channels are located in the optional first recess in the first part of the holder. The second ends of the plurality of channels are aligned with the corresponding inlets and outlets of the micro-fluidic device by placing the micro-fluidic device in the first recess, such that at least two vertical sides of the micro-fluidic device contact at least two vertical sides of the first recess in the first part of the holder. The sealing means between the plurality of inlets and the at least one outlet of the micro-fluidic device and the second ends of the plurality of channels in the first part of the holder not only ensures a fluid tight interconnection, but also decreases the required accuracy of the position (including the relative position between e.g. two inlets) and size of the plurality of inlets and the at least one outlet of the micro-fluidic device. The sealing means are provided with holes that on one side are connected to the second ends of the plurality of channels in the first part of the holder and on the other side to the plurality of inlets and the at least one outlet of the micro-fluidic device. These connections are however not made by fitting the sealing means in corresponding recesses in the micro-fluidic device and the first part of the holder. On the contrary, the connections are made by the earlier described surface contact between the micro-fluidic device and the sealing means and between the sealing means and the first part of the holder. The size of the holes in the sealing means determines the required accuracy of the (relative) position of the plurality of inlets and the at least one outlet of the micro-fluidic device: as long as the inlets and outlet(s) of the micro-fluidic device are located within the holes provided in the sealing means a fluid connection between the micro-fluidic device and the first part of the holder will be established. This embodiment provides an easy way of positioning the micro-fluidic device on the first part of the holder.

The at least one second recess enables easy positioning of the sealing means. The second recesses are of such shape and size that thermal expansion of the compressed sealing means (see above) is not restricted, such that permanent change of mechanical properties due to plastic deformation of the sealing material is prevented or at least mitigated. Preferably the at least one second recess is a shallow recess, the recess for example having a depth that is between 5%-40%, preferably between 6%-20%, more preferably between 7-15% smaller than the pre-compression thickness of the sealing means.

In an embodiment the micro-fluidic system according to the present invention, the planar micro-fluidic device has a thickness ti, the sealing means has a thickness X ₂ , the first recess has a depth d^ the at least one second recess has a depth d ₂ . The thicknesses and depths t|, X ₂ , ύ^ and d ₂ satisfy the formulas dτ+d ₂ ≤ X- _\ +X ₂ and 0<d ₂ ≤0.95 ^* t ₂ . The above ensures that the thickness of sealing means exceeds the depth of the at least one second recess, such that the sealing means can be compressed for at least 5% (of its original pre-compression thickness). The above also ensures that the holder is capable of clamping the micro-fluidic device and capable of exerting the desired pressure on the sealing means in order to reduce its thickness with at least 5% in compression.

In an embodiment the sealing means of the micro-fluidic system according to the present invention has a thickness t ₂ , the at least one second recess has a depth d ₂ . The thickness t ₂ and depth d ₂ satisfy the formula 0<d ₂ ≤0.95 ^* t ₂ , preferably 0.60 ^* t ₂ ≤d ₂ ≤0.95 ^* t _2l more preferably 0.70 ^* t ₂ <d ₂ ≤0.90*t ₂ , even more preferably 0.75*t ₂ ≤d ₂ ≤0.85*t ₂ . The above ensures that the pre-compression thickness of sealing means exceeds the depth of the at least one second recess, such that the sealing means can be compressed for at least 5% (of its pre-compression thickness), preferably between 5% and 40%, more preferably between 10% and 30%, even more preferably between 15% and 25% of its pre-compression thickness.

The selected range of the depth of the at least one second recess depends may also depend on the maximum elastic deformation of the selected material of the sealing means.

In an embodiment the first part of the holder is made of a material that is resistant against aggressive (e.g. corrosive) chemicals. Preferably the first part of the holder is manufactured of a polymeric material; the material for example comprises an epoxy polymer or polyaryletheretherketon (PEEK). PEEK is preferred as a material for the first part of the holder.

The first part of the holder may be a monolithic block provided with channels, or an assembly of layers. The latter has the advantage of easy cleaning and assembly.

In an embodiment the sealing means is of a chemically resistant, preferably elastic, material, for example comprising a perfluoroalkane polymer, preferably perfluoroethylene, e.g. Perlast®. The sealing means may comprise at least one O-ring. The O-rings connect the plurality of inlets and the at least one outlet of the micro-fluidic device with second ends of the plurality of channels in the first part of the holder. When the micro-fluidic device is clamped in the holder, the O-rings are deformed within their elastic region and provide a sealed connection.

In an embodiment the fixing means comprises a lid which is operatively connected to the first part of the holder and arranged to clamp the micro-fluidic device. The fixing may be achieved by any suitable releasable attachment means, including without limitation bolts and nuts or screw fixings, bayonet fittings whether quick release or not, push and snap fit connectors, vacuum or mechanical clamping connections, releasable mutually engageable resilient hook and feit pads, hooks, clips etc. The lid may be of a heat conducting material, for example steel. The advantage of a lid of a heat conducting material is better heat control of the micro-fluidic device. Another advantage of a steel lid is that the weight of it contributes to the clamping of the micro- fluidic device and allows stable positioning of the entire micro-fluidic system e.g. on a heating element, which may be in direct contact with the micro-fluidic device.

In an embodiment the micro-fluidic system comprises a plurality of connectors for connecting the first ends of the plurality of channels to a plurality of tubes. A plurality of tubes being arranged as feed tubes and being connected to the plurality of inlets of the micro-fluidic device. At least one of the plurality of tubes being connected to the at least one outlet of the micro-fluidic device. A typical connector may be a nut-and-ferrule connector.

The micro-fluidic device (a) may further comprise a reaction section (i.e. a micro-reactor) or a mixing section (i.e. a micro-mixer) or combinations thereof.

It is noted that the scope of the present invention is not limited to the above described embodiments. Combinations of features provides alternative embodiments according to the present invention.

A micro-fluidic system according to the present invention is suitable for use at a combination of high pressures at least up to 80 bar and high temperatures at least up to

200 ⁰ C. The suitable temperature range being between -20 ⁰ C and 200 ⁰ C, preferably between O ⁰ C and 195°C, more preferably between 80 ⁰ C and 190°C. The micro-fluidic system according to the present invention may therefore comprise a heater, which may directly heat the micro-fluidic device by being in direct contact with it. The micro-fluidic system may be used to mix aggressive chemicals or to perform chemical reactions that involve aggressive chemicals (e.g. corrosive chemicals).

The invention will now be explained in more detail with reference to the following figures:

Fig. 1A shows a schematic representation of a side view of a conventional micro-fluidic system;

Fig. 1 B shows the schematic representation of Fig 1 A after assembling;

Fig. 1C shows a schematic representation of a side view of a micro-fluidic system according to the present invention;

Fig. 1 D shows the schematic representation of Fig 1C after assembling;

Fig. 2A shows a schematic representation of a side view of an embodiment of the micro- fluidic system according to the present invention; Fig. 2B shows the schematic representation of Fig 2A after assembling;

Fig. 3 shows a schematic representation of a top view of the lid of the holder according to the present invention;

Fig. 4A shows a schematic representation of the top view of an O-ring;

Fig. 4B shows a schematic representation of the side view of the O-ring of Fig 4A;

Fig. 4C shows a schematic representation of the side view of the O-ring of Fig 4A and 4B in a deformed state.

A micro-fluidic system according to the present invention is schematically shown in Fig. 1A. The system comprises a holder, comprising a first part (1) and a lid (2). Both the first part and the lid are provided with holes (3a, 3a') and (3b, 3b') which enable both parts to be operatively connected by e.g. bolts (4a, 4b) and nuts (5a, 5b) as shown in Fig. 1 B. The fixing may be also be achieved by any other suitable releasable attachment means, e.g. screw fixings, bayonet fittings whether quick release or not, push and snap fit connectors, vacuum or mechanical clamping connections, releasable mutually engageable resilient hook and feit pads, hooks, clips etc.

The first part of the holder is a monolithic block made of polyaryletheretherketon (PEEK), the lid is monolithic block of steel. A top view of the lid is shown in Fig. 3. The lid (2) in this embodiment is provided with a window (12) and four holes to accommodate bolt-and-nut connections (23). The window allows easy access to the micro-fluidic device and limits heat leakage due to conduction by limiting the direct contact of the micro-fluidic device with the lid. Another advantage of this arrangement is that it enables heating the micro- fluidic device without excessive heating of the seals between the holder and the micro- fluidic device, which might lead to permanent deformation of the sealing means due to excessive thermal expansion and hence increases the risk of leakage of the micro-fluidic system. The above can be achieved by arranging the sealing means and a heating means at opposite sides of the window (12). The heating means may be arranged for example at number 8 in Figs 1A, 1 B, 1C, 1 D, 2A and 2B. The decoupling of heat transfer to the micro-fluidic device and heat transfer to the seals as described above further stretches the possible temperature operating window of the micro-fluidic system, because the seals do not reach the desired reaction temperature. The micro-fluidic device (8) is preferably made of glass, but in a less harsh chemical environment polymeric materials are also suitable, e.g. PMMA. In case the micro-fluidic device is a micro-mixer, the micro-fluidic device comprises at least two inlets, at least one outlet and a mixing region. If the micro-fluidic device is a micro-reactor, a plurality of inlets, preferably the number of inlets equals the number of reaction components, at least one out-let and a reaction region. For the present invention the interior of the micro-fluidic device is arbitrary and therefore not shown. The interior of the micro-fluidic device in the context of the present invention is considered a black box and indicated with (13). The micro-fluidic system further comprises sealing means (6) in this case at least one CD- ring. For convenience only one O-ring is shown, but it will be evident to the skilled person that in order to establish a plurality of connections between a plurality of inlets (one of which is indicated with number 7) and at least one outlet of the micro-fluidic device (8) and the second ends (9) of the channels (10), a plurality of O-rings will be present. Fig. 4A shows a schematic representation of the top view of an O-ring. Fig. 4B shows a schematic representation of the side view of the O-ring of Fig. 4A. It is noted that the cross-sectional area (14) of the O-ring shown in Fig 4B is circular. Suitable O-rings for the present invention are however not limited to such cross-sectional geometry. Other suitable cross-sectional geometries are (but is not limited to), e.g. square shaped, triangular, elliptical, star-shaped geometries. The sealing means are also not limited to O-rings. The top-view geometry (15) may also be (but is not limited to) e.g. elliptical, rectangular, etc. The sealing means are made of a chemically resistant material, preferably a perfluoro- elastomer, e.g. Perlast®. The first part of the holder (1 ) further comprises connectors (one of which is indicated with number 11) at the first ends (20) of the plurality of channels (10). Fig. 1A shows such a connector, which is known as a nut-and-ferrule connector. A conically shaped ferrule (16) holding a tube (17) is inserted in a counteracting conically shaped hole in the first part of the holder. A nut (18) is then screwed into the first part of the holder, which is provided with screw thread (19). The conically shaped ferrule expands, clamps the tube and thus provides a sealed connection between the first end of a channel and the tube. The nut- and-ferrule connector may also be combined into a single piece, and is made of chemically resistant materials, preferably PEEK.

Fig. 1 B shows the micro-fluidic system after assembling it. The required pressure to obtain a fluid tight connection that can withstand high pressures (up to 80 bar) is exerted by a number of bolt and nut connections (two of which are shown: 4a, 4b, 5a, 5b). The number of bolt-and-nut connections may however be varied. In certain cases even only one connection will suffice. The bolt and nut connections are made such that the sealing means are deformed such that the thickness of the sealing means is reduced with 5%- 40% dependent on the desired operating pressure of the micro-fluidic device.

Fig. 1C shows a schematic representation of a side view of a micro-fluidic system according to an embodiment of the present invention. The first part of the holder (1) comprises at least one second recess (22) provided for easy positioning of the sealing means. In the present case the second recesses are circular (not shown) to accommodate O-rings. The diameter of the second recesses is slightly larger than the diameter of the O- rings, to allow unrestricted mechanical and thermal expansion of the O-rings. This may be achieved if the ratio between the outer diameter of the at least one second recess and the original outer diameter of the O-ring is between 1.10 and 1.75, preferably between 1.15 and 1.5, more preferably between 1.20 and 1.4

Fig. 2A shows a schematic representation of a micro-fluidic system according to the present invention, provided with a first recess (21 ) for accommodating the micro-fluidic device. The first recess enables easy positioning and alignment of the micro-fluidic device on the first part of the holder. At least one second recess (22) is provided for easy positioning of the sealing means. In the present case the second recesses are circular (not shown) to accommodate O-rings. The diameter of the second recesses is slightly larger than the diameter of the O-rings, to allow unrestricted mechanical and thermal expansion of the O-rings.