DE102017127316A1 - Sample separator with microfluidic structure as a heat exchanger - Google Patents

Abstract

A sample separator (30) for separating a fluid sample in a sample separator (10), the sample separator (30) defining a wall (100) defining a lumen (102) for passing the fluid sample to separate the fluid sample, and a heat exchanger (104) has a formed microfluidic structure (106) in the wall (100).

Description

TECHNICAL BACKGROUND

 The present invention relates to a sample separator, a sample separator, a method for producing a sample separator, and a use.

In an HPLC, a liquid (mobile phase) is typically run at a very precisely controlled flow rate (for example in the range of microliters to milliliters per minute) and at a high pressure (typically 20 to 1000 bar and beyond, currently up to 2000 bar). , in which the compressibility of the liquid is felt, by a so-called stationary phase (for example in a chromatographic column), moved to separate individual components of a sample liquid introduced into the mobile phase from each other. Such an HPLC system is for example from EP 0,309,596 B1 by the same Applicant, Agilent Technologies, Inc.

 In a chromatographic sample separator, a chromatographic column as an example of a sample separator is often placed in a column oven where the column is heated. Nevertheless, it remains challenging to bring a fluidic sample or a mobile phase during the sample separation to a predeterminable and reproducible temperature. However, the production of such requirements fulfilling sample separation device for a sample separation device is still expensive. This is especially true if a compact sample separator is desired.

EPIPHANY

 It is an object of the invention to produce a powerful and compact sample separation device with reasonable effort. The object is achieved by means of the independent claims. Further embodiments are shown in the dependent claims.

 According to an exemplary embodiment of the present invention, there is provided a sample separator for separating a fluidic sample in a sample separator, the sample separator comprising a wall defining a lumen for passing the fluid sample to separate the fluid sample and a microfluidic structure formed as a heat exchanger in the sample Wall has.

 According to another exemplary embodiment, a sample separator is provided for separating a fluidic sample, the sample separator having a fluid drive for driving a mobile phase and the fluidic sample therein, and a sample separator having the above-described features for separating the fluid sample in the mobile phase ,

 According to yet another exemplary embodiment, there is provided a method of making a sample separator for separating a fluid sample in a sample separator, the method defining a wall defining a lumen for passing the fluid sample to separate the fluid sample, and one Heat exchanger configured microfluidic structure is formed in the wall.

 According to yet another exemplary embodiment, a sample separator having the features described above is used in chromatography, particularly in liquid chromatography (preferably in high temperature liquid chromatography or in subcritical water chromatography).

 In the context of the present application, the term "microfluidic structure" is understood in particular to mean a branched or unbranched channel, a plurality of such channels or another structure with dimensions in the range from micrometers to millimeters, which can be flowed through by fluid. According to one embodiment, an inner diameter of the at least one microfluidic structure may be in a range between 0.05 mm and 1 mm, in particular in a range between 0.1 mm and 0.5 mm. Preferably, the microfluidic structure is not elongated, but curved to provide the longest possible fluidic trajectory for effective heat exchange. The at least one microfluidic structure may in particular have at least one completely limited microfluidic channel. In other words, the microfluidic structure may be a microfluidic cavity in the wall.

 In the context of the present application, the term "lumen" is understood to mean, in particular, a preferably elongated channel which may have an inner diameter which is preferably greater than the inner diameter of the microfluidic structure. Preferably, the lumen is completely or partially filled with sample separation material for performing a sample separation, in particular a chromatographic sample separation.

According to an exemplary embodiment, a sample separation device (for example a chromatographic separation column) is provided, in which a heat exchanger is integrated in a wall or a column body. More specifically, a microfluidic structure is in the wall is formed, through which fluid (in particular a fluidic sample to be separated and / or a mobile phase) can be passed in order to get during this passage in thermal communication with another fluid (in particular another part of the fluidic sample or another mobile phase) which flows through the lumen bounded by the wall. In other words, for example, a fluid can first be guided through the microfluidic structure in the wall, in the meantime in thermal exchange with fluid in the interior of the lumen. Thereafter, the former fluid can be introduced into the lumen. In this way, a sample separator with integrated heat exchanger is provided which can be formed in a compact manner to introduce thermally conditioned samples or solvents into the lumen of the sample separator. This increases the reproducibility and accuracy of sample separation in the sample separator. The fluid flowing through the microfluidic structure and / or the lumen may be a fluidic sample and / or another fluid, for example a mobile phase in the form of a solvent or a solvent composition. In a chromatographic separation process, the fluidic sample can also be transported in such a mobile phase.

In addition, additional embodiments of the sample separation device, the sample separation device, the method and the use will be described.

 According to one embodiment, the wall can be integral and even single-material and form the microfluidic structure in that a mere corresponding recess is formed in the wall.

 According to one embodiment, the wall may comprise a plurality of bonded, in particular metallic, layers, between which the microfluidic structure is formed by means of a structured one of the layers. According to such an embodiment, the wall may be formed with the microfluidic structure by connecting several, in particular metallic, layers, of which at least one is microstructured, by bonding, in particular by diffusion bonding, to form an integral layer stack and the layer stack to form the lumen is deformed. It is thus possible, in particular, to provide a plurality of metallic layers (for example stainless steel platelets) which can be integrally connected to one another. If one or both of the mutually facing metallic layers contains a microfluidic structure, the microfluidic structure in the area between the layers can be limited. For example, the sample separator may be formed by micro metal structures.

 According to one embodiment, the wall may be formed with the microfluidic structure by means of additive manufacturing, in particular by means of three-dimensional printing. In the context of the present application, the term "additive manufacturing" or additive manufacturing can be understood to mean processes for the constructive production of bodies which, for example, are based directly on, for example, a computer-internal data model of informal starting materials (for example a suspension , an emulsion, liquids, gels, pastes, powders, etc.) or form neutral (for example ribbon, wire, sheet) material can be made by chemical and / or physical processes. Although they are often forming processes, additive manufacturing does not require tools that are shaped according to the particular geometry of the body to be generated (eg, molds). Examples of additive manufacturing processes are powder bed processes, free space processes, liquid material processes and other layer construction processes, three-dimensional printing, etc.

 According to such an embodiment, the wall may be formed with the microfluidic structure, in particular by means of selective solidification of a suspension of ceramic particles and a binder curable by means of electromagnetic radiation. Three-dimensional printing can also be used to delineate microfluidic structures based on a suspension or a powder as starting material. For example, a laser may selectively solidify regions of such a suspension or powder to thereby define regions of the wall. Non-solidified areas of the suspension or the powder can then be removed, for example, by rinsing or by means of compressed air from the microfluidic structures formed, so that only the wall with the microfluidic structures remains behind.

According to one embodiment, the wall may be formed by means of at least two telescoped and interconnected tubes, of which at least one tube forms at least one part of the microfluidic structure at a contact surface to a respective other of the tubes. According to such an embodiment, the wall may be made with the microfluidic structure by telescoping and interconnecting two tubes, wherein at least one of the tubes has the microfluidic structure at one contact surface to another of the tubes. By two to each other corresponding tubes are slipped on each other and then shrunk onto each other, for example, microfluidic structures can be formed between the tubes if one or both of the corresponding tube surfaces has such microfluidic structures. For example, an external thread of an inner tube together with a smooth inner surface of an outer tube can form a helical microfluidic structure in the area of the interconnected contact surfaces.

 According to one embodiment, the microfluidic structure formed as a heat exchanger may be configured to effect a heat exchange between a fluid flowing through the lumen and a fluid flowing through the microfluidic structure. The heat exchange is mediated by the material of the wall. By means of this heat exchange and an associated temperature compensation, a sample separation can be carried out under precisely defined conditions. This has advantages for the accuracy and reproducibility of a chromatographic separation.

 According to one embodiment, the microfluidic structure and the lumen may be fluidly connected to one another. In particular, they may be serially fluidly connected to one another such that a fluid flowing into the sample separator first passes through the microfluidic structure for heat exchange and then through the lumen for sample separation, for example. A fluidic sample and / or a mobile phase can then be exposed to heat exchange with a fluidic sample and / or mobile phase in the lumen first during flow through the microfluidic structure, and can subsequently flow into the lumen in a pre-tempered manner. As it flows into the lumen, the fluidic sample may be adsorbed to the sample separation material and may then be fractionally detached from the sample separation material, for example, by adjusting a corresponding mobile phase solvent composition.

 According to an exemplary embodiment, the microfluidic structure and the lumen may be configured to transport a fluid flowing in at an inlet of the sample separator through the microfluidic structure to an exit, from the exit through the microfluidic structure back in the circumferential direction to the inlet and away from the inlet Entrance into the lumen to flow through it to introduce. As a result, the fluid (in particular fluidic sample and / or mobile phase) is exposed to a defined flow path, along which initially a heat exchange and then a sample separation can take place.

 According to one exemplary embodiment, at least part of the microfluidic structure may be formed as a meander structure and / or a helical structure. It is also possible for the microfluidic structure to be formed in sections as a meandering structure, where a fluid traverses a zigzag-shaped trajectory, and in sections as a helical structure, where a fluid passes through a circumferential (for example helical) trajectory. Both a meander structure and a helical structure, as well as a combination thereof, make it possible to increase the path to be traveled by the fluid as it traverses the microfluidic structure, as opposed to a linear path, thus improving heat exchange.

 According to one embodiment, the sample separator may include a heater that is thermally coupled to the wall. In this way, not only a heat exchange, but also a preheater can be integrated into the sample separator. The heater may be integrated in the wall or provided separately therefrom.

 According to an embodiment, the heater may surround an outer surface of the wall. If the heating device surrounds the outer surface of the wall, it can be easily applied, for example printed or vapor-deposited, after the wall has been produced. It is also possible to wind the heating device around the wall, for example in the form of a heating wire or a heating foil. The heater can therefore be an ohmic resistance heater. Other forms of heating, such as providing a heated fluid that passes around the wall along a capillary, are also possible.

 According to one embodiment, the heating device may be formed as at least one of a group, which consists of a deposited on the wall (in particular sputtered) heating structure and placed on the wall (in particular wound) heating structure. Both sputtering and winding a heating structure are possible with little effort and allow reliable heat transfer from the heater to the fluid flowing through the sample separator.

 The heating device can be provided in such a way that the fluid flowing through the microfluidic structure is tempered by means of the heating device.

According to one embodiment, the lumen may be at least partially filled by a sample separation material. Such a sample separating material may be a stationary phase in one Sample Separator (for example, a chromatographic column). Such a sample separation material may contain beads to which fractions of a fluidic sample may be fractionally adsorbed and redissolved (for example, by changing the chemical environment by supplying a solvent). For example, peeling may occur as part of a chromatographic gradient run by a successive change in a mobile phase solvent composition passed through the sample separator after the individual fractions of the fluidic sample have been absorbed on the sample separator due to their respective physical and chemical properties.

 According to one embodiment, a frit may be arranged at an entrance and / or at an exit of the lumen. Such a frit can be, for example, a filter made of glass or ceramic, which can be used to filter even the finest particles. The glass or ceramic is preferably porous so that the material to be filtered will stick in the pores as in a very fine sieve. For example, a frit may be a sintered body through which fluid flows at the inlet and at the outlet. Such a frit can prevent rinsing of sample separation material from the sample separation device and can also serve as a filter at the entrance of the sample separation device.

 According to one embodiment, the sample separation device may comprise a thermally insulating outer shell. If a thermally insulating outer shell is provided, heat losses to the outside can be kept low. Alternatively, the sample separator may be arranged as a whole in a column oven or the like of a sample separator. Then the thermally insulating outer sleeve can also be omitted.

 According to an embodiment, the wall may comprise at least three bonded metal layers. Two opposite outer surfaces of the wall-forming metal layers may be free of structuring, i. For example, they may be formed as continuous metal layers. On the other hand, at least one interposed metal layer may be patterned to form the microfluidic structure, i. in particular be provided with a groove-shaped recess or with a corresponding through hole. In this way, by structuring only a single metal layer, in principle, a microfluidic structure of arbitrarily complex shape can be produced, which can be bounded on the outside by the two full-area metal layers.

 According to one exemplary embodiment, the microfluidic structure can be produced by means of a lithography and etching method, by means of a laser processing method or by means of a mechanical removal method. In particular, a continuous layer (for example of a metal) may be patterned with a lithography and etching process to form channels. Subsequently, this metal layer can be connected on one or both opposite sides with a further metal layer, in particular by means of diffusion bonding, to thereby form an integral wall structure. However, ablation of layer material to form the microfluidic structure can also be carried out by means of a laser or mechanically (for example by milling, drilling, etc.).

 According to one embodiment, the wall may first be produced as a planar layer or as a planar layer stack which is subsequently rolled up to form the lumen. Processing the wall in planar geometry is particularly easy to precisely form the microfluidic structures. Subsequent rolling allows the transfer of the bonded layers with integrated microfluidic structure into a closed hollow cylindrical wall which can serve for the circumferential fluidic confinement of the sample separator.

 According to one embodiment, after rolling up, the rolled-up layer can be joined in a connection area or at the joint, in particular by means of welding, gluing, soldering, etc. If a layer stack is rolled up, an unconnected location is created in the region of the two ends. If welded there or otherwise materially connected, can be completed with simple means reliably the sample separator.

According to an embodiment, in forming the wall, a rectangular layer stack may be made with a circular projection, the rectangular layer stacks rolled to form the wall with the lumen, and the circular projection folded over to at least partially close one end of the rolled layer stack. In this way, also an end closure of the sample separator can be made integral with the formation of micro metal structures by subjecting a correspondingly structured layer stack having a rectangular main section and a circular end section to a simple bending after being rolled up.

According to one embodiment, the separation device can be used as a chromatographic separation device, in particular as Chromatographietrennsäule be formed. In a chromatographic separation, the chromatographic separation column may be provided with an adsorption medium. At this, the fluidic sample can be stopped and only then with appropriate eluent (isocratic) or in the presence of a specific solvent composition (gradient) fractionally detached again, thus the separation of the sample is accomplished in their fractions.

 The sample separation device may be a microfluidic measuring device, a life science device, a liquid chromatography device, a high performance liquid chromatography (HPLC), a UHPLC system, an SFC (Supercritical Liquid Chromatography) device, a gas chromatography device, an electrochromatography device, and / or a gel electrophoresis device , However, many other applications are possible.

 For example, the fluid pump may be configured to convey the mobile phase through the system at a high pressure, for example, from a few hundred bars up to 1000 bars or more.

 The sample separator may include a sample injector for introducing the sample into the fluidic separation path. Such a sample injector may comprise a syringe-dockable injection needle in a corresponding fluid path, which needle may be withdrawn from that seat to receive sample, wherein upon reintroduction of the needle into the seat, the sample is in a fluid path which, for Example, by switching a valve, can be switched into the separation path of the system, which leads to the introduction of the sample in the fluidic separation path.

 The sample separator may include a fraction collector for collecting the separated components. Such a fraction collector may carry the various components, for example, into different liquid containers. The analyzed sample can also be fed to a drain tank.

 Preferably, the sample separation device may comprise a detector for detecting the separated components. Such a detector may generate a signal which can be observed and / or recorded and which is indicative of the presence and amount of sample components in the fluid flowing through the system.

BRIEF DESCRIPTION OF THE FIGURES

 Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following more particular description of embodiments taken in conjunction with the accompanying drawings. Features that are substantially or functionally the same or similar are given the same reference numerals.

1 shows an HPLC system as a sample separation device according to an exemplary embodiment of the invention.

2 shows a sample separator according to an exemplary embodiment of the invention.

3 shows a cross-sectional view of the sample separator according to 2 ,

4 shows a preform of the sample separator according to 2 ,

5 shows a layer stack of the sample separator according to 2 ,

6 shows a preform of a sample separator according to an exemplary embodiment of the invention.

7 shows a preform of a sample separator according to another exemplary embodiment of the invention.

8th to 10 show a produced by additive manufacturing sample separation device according to an exemplary embodiment of the invention.

11 shows an apparatus for manufacturing a sample separator by means of additive manufacturing according to an exemplary embodiment of the invention.

12 shows a manufacturing of a sample separator by connecting two tubes according to an exemplary embodiment of the invention.

 The illustration in the drawings is schematic.

Before describing exemplary embodiments with reference to the figures, some basic considerations will be summarized based on those exemplary embodiments of the invention have been derived.

In a (for example chromatographic) sample separation device, it is advantageous to temper a solvent (also referred to as mobile phase) and / or a fluidic sample (that is to say the sample actually to be separated) upstream and / or downstream of a sample separation device, on the one hand the sample separation to be able to perform at a defined temperature and, on the other hand, to prepare the fluid to a detector temperature downstream of the sample separator. This allows effective suppression of adiabatic disturbances during sample separation.

 According to an exemplary embodiment of the invention, a micro-metal structure is created in a wall of a sample separator to allow for heat exchange between fluid flowing through the microfluidic structure and fluid flowing through the lumen of the sample separator. For this purpose, a roller can be rotated from a layer stack whose wall contains the microfluidic structure and the lumen can be filled with sample separation material. In other words, according to an exemplary embodiment, a sample separation device, in particular in the form of a chromatographic separation column, can be provided with a microfluidic structure which functions as a heat exchanger in the column wall.

 The production of such a sample separator can, as already mentioned, be effected by means of micro metal structures. Alternatively, such a column wall with integrated microfluidic structure can also be produced by three-dimensional printing or another form of additive manufacturing. Furthermore, it is possible to make such a wall from two or more tubes, wherein an outer tube is shrunk onto an inner tube and thereby a channel structure between the outer and the inner tube (for example by a thread on an outer surface of the inner tube and / or on an inner surface of the outer tube) is generated.

 In HPLC, columns are conventionally made from a solid-state tube. The wall of the column is so thick that it can withstand the pressures generated during operation without being damaged or destroyed. To heat a column, convection with heated air, preheating of the solvent prior to flowing into the column and / or direct coupling of the column to heating elements is possible. Such conventional heating principles often fail to produce a desired temperature gradient sufficiently quickly without coupling dissipative effects. Also, supplying a correspondingly high heating energy is conventionally difficult.

 Therefore, according to an exemplary embodiment, a heat exchanger for preheating the solvent and a column body for guiding a fluid in an axial lumen may be integrally formed within the heat exchanger. Also, a corresponding sample separator can be provided with a heating element. Using micro metal fluidic technology, it is possible to roll a patterned metal sheet into a tube into which preheat functionality can be integrated. In this way, a less expensive solution can be obtained than a conventional column oven. Further, it is possible to implement a combination of preheating a solvent and heating the column to achieve direct temperature balance of the column. In particular, according to exemplary embodiments, it is also possible to heat faster and / or to higher temperatures and thus to set fast temperature gradients. Since the temperature of the column and mobile phase affect chromatographic retention, a temperature gradient can also be used to elute fractions of a sample from the column. For example, a temperature gradient may replace or supplement a solvent gradient. Preferred application areas of exemplary embodiments are HTLC (High Temperature Liquid Chromatography) or SBWC (Subcritical Water Chromatography).

 Exemplary embodiments have the advantage that an elevated temperature range of up to 400 ° C and more can be achieved without a high energy requirement for the heating. The latter can be achieved by the thermal insulation described above. By programming a temperature gradient, the amount of organic solvent in the mobile phase can be reduced to adjust retention. Exemplary embodiments also make it possible to use only water at elevated temperature for separation. An organic solvent can then be completely or partially dispensable. Moreover, according to exemplary embodiments, it is possible to more quickly achieve a thermal equilibrium state and thereby reduce the time for analysis than is conventionally the case. It is also possible to set isothermal conditions in the sample separation device instead of adiabatic conditions.

1 shows the basic structure of an HPLC system as an example of a sample separator 10 as it is for example Liquid chromatography can be used. A fluid pump as a fluid drive 20 containing solvents from a supply unit 25 supplied drives a mobile phase through a sample separator 30 (such as a chromatographic column) containing a stationary phase. A degasser 27 can degas the solvents before they drive the fluid 20 be supplied. A sample application unit 40 with a switching valve or fluid valve 95 is between the fluid drive 20 and the sample separator 30 arranged to introduce a sample liquid in the fluidic separation path. The stationary phase of the sample separator 30 is intended to separate components of the sample. A detector 50 , for example comprising a flow cell, detects separated components of the sample. A fractionator 60 may be provided to dispense separated components of the sample in dedicated containers. Liquids no longer needed can be dispensed into a drain tank.

A control unit 70 controls the individual components 20 . 25 . 27 . 30 . 40 . 50 . 60 . 95 of the sample separator 10 ,

At the sample separator 30 are microfluidic channels or structures 106 in a substantially hollow cylindrical wall 100 integrated fluid lines through which a mobile phase or a fluidic sample can flow. This is in 1 in a detail 179 shown schematically. To effect a heat balance of one through the sample separator 30 flowing fluid first flows from an input 116 the sample separator 30 towards an exit 118 the sample separator 30 , from there (for example, along an in 1 not shown in detail helical or meandering river paths) back towards the entrance 116 and then from there through chromatographic sample separation material 122 straight in one of the wall 100 circumferentially limited central lumen 102 radially within the microfluidic structure 106 back to the exit 118 to flow where the fluid is the sample separator 30 leaves (see the in the detail 179 schematically indicated trajectory in which arrows indicate the direction of flow).

In the 1 schematically shown sample separation device 30 for separating a fluidic sample in the sample separator 10 has the wall 100 on that the lumen 102 limited to performing the fluidic sample for separating the fluidic sample. The as a heat exchanger 104 formed microfluidic structure 106 is in the wall 100 integrated.

A fluid (for example, the mobile phase and / or the fluidic sample) flows (as shown in the schematic illustration) 1 can not be seen in detail) when passing through the sample separator 30 preferably initially helical within the wall 100 the sample separator 30 and then flows through the lumen 102 inside the wall 100 the sample separator 30 straight through. During helical movement along an elongated trajectory, heat exchange occurs between the helically circulating fluid in the microfluidic structure 106 and the longitudinal fluid in the lumen 102 by good heat conductive material of the wall 100 , During the longitudinal flow along the lumen 102 then the fluid flows through the sample separator 30 , In this way is in the sample separator 30 integrated a heat exchange function.

2 shows a sample separator 30 according to an exemplary embodiment of the invention. 3 shows a cross-sectional view of the sample separator 30 according to 2 , 4 shows a preform of the sample separator 30 according to 2 as obtained during a manufacturing process. 5 shows a layer stack of sample separation device 30 according to 2 as obtained during a manufacturing process.

At the in 2 to 5 Sample separator shown 30 is the wall 100 through three bonded metallic layers 108 formed (see 3 ), between which a cavity as a microfluidic structure 106 by structuring a central one of the three layers 108 is trained. The as a heat exchanger 104 formed microfluidic structure 106 in the wall 100 is also designed to heat exchange between one through the lumen 102 flowing fluid and through the microfluidic structure 106 flowing fluid to accomplish, with a heat flow through the thermally conductive wall 100 can be taught.

For this purpose, the microfluidic structure 106 trained, one at the entrance 116 the sample separator 30 inflowing fluid through the microfluidic structure 106 to the exit 118 to transport from the exit 118 through the microfluidic structure 106 back in the circumferential direction to the entrance 116 attributed and in the area of the entrance 116 into the lumen 102 introduce. More specifically, see 4 , the fluid from the entrance 116 straight ahead towards the exit 118 promoted and then circulating through the microfluidic structure 106 to a lumen entrance 116 ' near the entrance 116 recycled. During this circulation, the heat exchange takes place. At the lumen entrance 116 ' the fluid then flows into the lumen 102 and leaves after flowing through the lumen 102 this and the sample separator 30 as a whole at the exit 118 ,

Advantageously, the microfluidic structure 106 be formed as a mixture of a meander structure and a helical structure. Such a mixed structure is obtained when the in 4 shown layer stack to a hollow circular cylindrical structure bent (for example, rolled up) is.

A heating device 120 the sample separator 30 can with the wall 100 be thermally coupled. Preferably, the heater surrounds 120 an outer surface of the wall 100 , For example, the heater 120 be a sputtered heating structure or a wound heating structure, each of which allows ohmic heating.

To a fluidic sample as it flows through the lumen 102 to be able to separate is the lumen 102 with a chromatographic sample separation material 122 filled. At the entrance 116 and at the exit 118 of the lumen 102 is in each case a frit formed, for example, as a sintered body 124 arranged.

Furthermore, the sample separator 30 according to 2 to 5 a thermally insulating outer shell 126 up, see 3 , This can be made, for example, from a ceramic.

In the illustrated embodiment, as best shown in FIG 5 and 4 you can see the wall 100 through three bonded metal layers 108 formed, of which the two outer of a structuring are free and arranged therebetween middle metal layer 108 for forming the microfluidic structure 106 is structured. More specifically, in the described embodiment, the wall 100 with the microfluidic structure 106 made by the three mentioned metallic layers 108 of which the middle is microstructured by means of diffusion bonding together to form an integral layer stack 130 be connected and the layer stack 130 to make the lumen 102 is rolled to a hollow cylinder. Therefore, the wall can 100 are first prepared as a flat layer, then forming the lumen 102 being rolled up. After rolling, the rolled up layer can be welded at a joint. The microfluidic structure 106 can be in the central metal layer 108 For example, be prepared by means of a lithography and etching process or by means of a Laserprozessierverfahrens.

Advantageously, when making the wall 100 First, a best in 4 to be recognized rectangular stack of layers 130 with a circular approach 136 getting produced. Subsequently, the rectangular layer stack 130 for forming the hollow cylindrical wall 100 with the lumen 102 to be rolled and the circular approach 136 for closing one end of the rolled layer stack 130 be folded.

2 shows a side view of the entire sample separator 30 with integrated heat exchanger 104 , integrated preheating (see reference number 120 ) and integrated thermal insulation sheath (see reference numeral 126 ). 3 shows a cross-sectional view through the individual layers of the sample separator 30 , 4 shows how the integral metal layers 108 the wall 100 can be formed by structuring and bonding to the microfluidic structure 106 to build. The substantially rectangular configuration according to 4 can then be rolled up to the finished sample separator 30 according to 2 and 3 to obtain. After rolling up and welding along a joint then the circular extension 136 be folded down to one end of the sample separator 30 to close.

5 shows by means of diffusion bonding bonded micro metal structures in the form of the metal layers made of stainless steel 108 which are integrally connected with each other.

The embodiment according to 2 to 5 allows the sample separator 30 as well as processed therein fluid (in particular solvent and fluidic sample) quickly to convert into a stable thermal target state. In particular, this allows driving fast temperature gradients (for example, for a chromatographic separation without organic solvent). A corresponding sample separator 30 can also be manufactured with low production costs.

6 shows a preform of a sample separator 30 according to another exemplary embodiment of the invention. 7 shows a preform of a sample separator 30 according to another exemplary embodiment of the invention.

6 and 7 show that channel geometries other than those according to 4 shown are possible. According to 6 performs the fluid as it passes through the microfluidic structure 106 after rolling up the layer stack shown there, a circumferential movement between the input 116 and exit 118 , In the configuration according to 7 places the fluid when passing through the microfluidic structure shown there 106 several times the way back between the beginning of the column and the end of the column and flows in Substantially parallel or antiparallel to that through the lumen 102 flowing fluid. Due to the configurations according to 6 and 7 In particular, a low heat capacity can be achieved due to the fact that an additional layer for pressure stability can be dispensable. Also, there is no fear of additional thermal resistance (for example, due, for example, to air gaps) between the flow path and the heating element.

The embodiments shown may be a heat exchanger 104 in a sample separator 30 implement, which can be formed with very different micro metal fluidic structures. A specially configurable configuration of the geometry of the microfluidic structure 106 allows the sample separator 30 to apply certain thermal effects. It is also possible, according to exemplary embodiments, the entire sample separator 30 stable with a relatively low amount of energy.

8th to 10 show a prepared by additive manufacturing sample separation device 30 according to an exemplary embodiment of the invention.

8th shows a helical heat exchanger 104 , for example, by means of three-dimensional printing in the wall 100 the sample separator 30 can be generated. According to 9 is this microfluidic structure 106 inside a three-dimensionally produced (for example, three-dimensionally printed) body in the form of the wall 100 shown. 10 shows an overview of constituents according to 9 and 8th ,

11 shows an apparatus 177 for producing a sample separator 30 by additive manufacturing according to an exemplary embodiment of the invention. In other words, in 11 represented as the wall 100 with the microfluidic structure 106 can be prepared by additive manufacturing. More specifically, according to 11 the wall 100 with the microfluidic structure 106 by means of selective solidification of a suspension 181 made of ceramic particles 132 with a curable by electromagnetic radiation binder 134 trained (see detail 230 ).

11 shows a container 200 with the suspension 181 from the ceramic particles 132 (For example, alumina)) and the binder 134 , A carrier table 204 is movable (see double arrow 206 ) in the container 200 arranged. A laser 128 (or other electromagnetic radiation source) may be a traveling one (see reference numeral 299 ) Laser beam 208 on selectable sections of the suspension 181 in order to solidify these selectively or selectively. If the carrier 204 in the area of a surface 199 the suspension 181 can be arranged, a lowest layer 210 the wall 100 by means of the laser 128 solidified and thus produced. In those areas where the laser 128 no suspension 181 solidified, arise or remain the microfluidic structures 106 , After making the first layer 210 becomes the carrier 204 lowered down, by means of the laser 128 a second layer 214 the wall 100 processed, then a third shift 216 , etc. 11 shows an operating condition of the apparatus 177 for producing the sample separator 30 , at the moment the third shift 216 the wall 100 is trained or defined.

Although not shown in the figure, the wall can 100 after making all his layers 210 . 214 . 216 , etc. from the container 200 are removed, cleaned and optionally subjected to a combustion process to complete the preparation of the sample separator.

12 shows a manufacturing a sample separator 30 by connecting two pipes 110 . 112 according to an exemplary embodiment of the invention.

According to 12 becomes the wall 100 by means of two telescoped and interconnected pipes 110 . 112 formed, of which a pipe 110 at a contact surface 114 to another pipe 112 the microfluidic structure 106 forms. For this purpose, the tube points 112 at a contact surface 114 to the other tube 110 the microfluidic structure 106 on. The one-piece wall 100 with the microfluidic structure 106 is thus prepared according to the described embodiment, by the two tubes 110 . 112 pushed into each other and connected to each other.

In the embodiment according to 12 So these are the two pipes 110 . 112 provided, wherein, as with reference numerals 260 shown, the inner diameter of the tube 110 approximately the outer diameter of the tube 112 equivalent. As with arrow 275 shown, the pipe becomes 112 in the interior of the pipe 110 pushed and then shrunk on (for example, thermally). Because the outer surface of the pipe 112 with an external thread 280 is provided, the inner surface of the tube 110 however, is smooth, leads a connecting the pipes 110 . 112 in the manner described, that the external thread 280 together with the opposite smooth surface of the pipe 110 the microfluidic structure 106 in the wall 100 the prepared sample separation device 30 forms.

It should be noted that the term "comprising" does not exclude other elements and that the "one" does not exclude a plurality. Also, elements described in connection with different embodiments may be combined. It should also be noted that reference signs in the claims should not be construed as limiting the scope of the claims.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 0309596 B1 [0002]

Claims (20)

Sample separation device ( 30 ) for separating a fluidic sample in a sample separation device ( 10 ), the sample separation device ( 30 ): a wall ( 100 ), which is a lumen ( 102 ) for conducting the fluidic sample to separate the fluidic sample; as a heat exchanger ( 104 ) formed microfluidic structure ( 106 ) in the wall ( 100 ). Sample separation device ( 30 ) according to claim 1, wherein the wall ( 100 ) a plurality of bonded, in particular metallic, layers ( 108 ) between which the microfluidic structure ( 106 ) by means of at least one structured layer ( 108 ) is trained. Sample separation device ( 30 ) according to claim 1, wherein the wall ( 100 ) with the microfluidic structure ( 106 ) is formed by additive finished, in particular by means of three-dimensional printing. Sample separation device ( 30 ) according to claim 1, wherein the wall ( 100 ) by means of at least two telescoped and interconnected tubes ( 110 . 112 ) is formed, of which at least one tube ( 110 ) at a contact surface ( 114 ) to a respective other of the tubes ( 112 ) at least part of the microfluidic structure ( 106 ). Sample separation device ( 30 ) according to one of claims 1 to 4, wherein the heat exchangers ( 104 ) formed microfluidic structure ( 106 ), a heat exchange between a through the lumen ( 102 ) flowing fluid and through the microfluidic structure ( 106 ) fluid to accomplish. Sample separation device ( 30 ) according to one of claims 1 to 5, wherein the microfluidic structure ( 106 ) and the lumen ( 102 ) are fluidly connected to each other, in particular, are serially fluidly connected to one another such that a in the sample separation device ( 30 ) flowing fluid first the microfluidic structure ( 106 ) to the heat exchange and then the lumen ( 102 ) goes through. Sample separation device ( 30 ) according to one of claims 1 to 6, wherein the microfluidic structure ( 106 ) and the lumen ( 102 ), one at an entrance ( 116 ) of the sample separation device ( 30 ) inflowing fluid through the microfluidic structure ( 106 ) towards an exit ( 118 ), from there through the microfluidic structure ( 106 ) back in the circumferential direction towards the entrance ( 116 ) and then from there into the lumen ( 102 ) introduce. Sample separation device ( 30 ) according to one of claims 1 to 7, wherein at least part of the microfluidic structure ( 106 ) is designed as a meander structure and / or helical structure. Sample separation device ( 30 ) according to one of claims 1 to 8, comprising a heating device ( 120 ), with the wall ( 100 ) is thermally coupled. Sample separation device ( 30 ) according to claim 9, wherein the heating device ( 120 ) an outer surface of the wall ( 100 ) surrounds. Sample separation device ( 30 ) according to claim 9 or 10, wherein the heating device ( 120 ) is formed as at least one of a group consisting of one on the wall ( 100 ) deposited, in particular sputtered, heating structure and one on the wall ( 100 ) fitted, in particular wound, heating structure. Sample separation device ( 30 ) according to one of claims 1 to 11, comprising a sample separation material ( 122 ), with which at least a part of the lumen ( 102 ) is filled. Sample separation device ( 30 ) according to one of claims 1 to 12, comprising at least one frit ( 124 ) at an entrance ( 116 ) and / or at an output ( 118 ) of the lumen ( 102 ) is arranged. Sample separation device ( 30 ) according to one of claims 1 to 13, comprising at least one of the following features: comprising a thermally insulating outer shell ( 126 ); where the wall ( 100 ) at least three bonded metal layers ( 108 ), of which outer surfaces of the wall ( 100 ) forming metal layers ( 108 ) are free of structuring and at least one interposed metal layer ( 108 ) for forming the microfluidic structure ( 106 ) is structured. Sample Separator ( 10 ) for separating a fluidic sample, wherein the sample separation device ( 10 ) comprises: a fluid drive ( 20 ) for driving a mobile phase and the fluidic sample therein; a sample separator ( 30 ) according to one of claims 1 to 14 for separating the fluidic sample in the mobile phase. Sample Separator ( 10 ) according to claim 15, further comprising at least one of the following features: the sample separator ( 30 ) is designed as a chromatographic separation device, in particular as a chromatography separation column; the sample separator ( 10 ) is configured to analyze at least one physical, chemical and / or biological parameter of at least one fraction of the fluidic sample; the sample separator ( 10 ) comprises at least one of the group consisting of a chemical, biological and / or pharmaceutical analysis apparatus and a chromatographic apparatus, in particular a liquid chromatography apparatus, a gas chromatography apparatus, a supercritical liquid chromatography apparatus, an HPLC apparatus and a UHPLC apparatus; the fluid drive ( 20 ) is configured to drive the mobile phase at a high pressure; the fluid drive ( 20 ) is configured to drive the mobile phase at a pressure of at least 100 bar, in particular at least 500 bar, more particularly at least 1000 bar; the sample separator ( 10 ) is configured as a microfluidic device; the sample separator ( 10 ) is configured as a nanofluidic device; the sample separator ( 10 ) has a sample application unit ( 40 ) for introducing the fluidic sample into a fluidic path between the fluid drive ( 20 ) and the sample separation device ( 30 ) on; the sample separator ( 10 ) has a detector ( 50 ), in particular a fluorescence detector or UV absorption detector, for detecting the separated fluidic sample; the sample separator ( 10 ) has a sample fractionator ( 60 ) for fractionating the separated fluidic sample. Method for producing a sample separator ( 30 ) for separating a fluidic sample in a sample separation device ( 10 ), the method comprising: forming a wall ( 100 ), which is a lumen ( 102 ) for conducting the fluidic sample to separate the fluidic sample; Forming a heat exchanger ( 104 ) configured microfluidic structure ( 106 ) in the wall ( 100 ). Method according to claim 17, comprising one of the following features: wherein the wall ( 100 ) with the microfluidic structure ( 106 ) is formed by several, in particular metallic, layers ( 108 ), of which at least one is microstructured, by bonding, in particular by means of diffusion bonding, together to form an integral layer stack ( 130 ) and the layer stack ( 130 ) for forming the lumen ( 102 ) is deformed; where the wall ( 100 ) with the microfluidic structure ( 106 ) by means of additive finishing, in particular by means of selective solidification of a suspension of ceramic particles ( 132 ) with a by means of electromagnetic radiation curable binder ( 134 ) is formed; where the wall ( 100 ) with the microfluidic structure ( 106 ) is made by pipes ( 110 . 112 ) are pushed together and connected to each other, wherein at least one of the tubes ( 110 ) at a contact surface ( 114 ) to another of the pipes ( 112 ) at least part of the microfluidic structure ( 106 ) having. A method according to claim 17 or 18, comprising at least one of the following features: wherein the microfluidic structure ( 106 ) is produced by a lithography and etching process, by a laser processing method, or by a mechanical abrasion method; wherein for forming the wall ( 100 ) first a flat layer stack ( 130 ), which is then formed to form the lumen ( 102 ) is rolled up, wherein in particular after rolling up the rolled-up layer stack ( 130 ) is connected in a connection region, in particular by means of welding; wherein during the manufacture of the wall ( 100 ) a rectangular layer stack ( 130 ) with a circular approach ( 136 ), the rectangular layer stack ( 130 ) for forming the wall ( 100 ) with the lumen ( 102 ) and the circular approach ( 136 ) for at least partially closing one end of the rolled layer stack ( 130 ) is folded. Use of a sample separator ( 30 ) according to one of claims 1 to 14 in chromatography, in particular in liquid chromatography, more particularly in high temperature liquid chromatography or in subcritical water chromatography.

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