DE102008002156A1 - Biochip, for the manipulation of micro-fluids, has wells in groups in and/or on a substrate with linking channels and long separation channels - Google Patents

Abstract

The biochip (100) for manipulating a fluid, in a life science apparatus, has a number of wells (104) to hold the fluid in and/or on a substrate (102). At least one channel (106), in and/or on the substrate links the wells together in groups (110,112,114,116). The longest channel is a separation channel (108). All the linked wells lie exactly on a common direction. The substrate can be of glass, plastics, metal, ceramic or a semiconductor.

Description

TECHNICAL BACKGROUND

The The present invention relates to chips for a life science device.

gel electrophoresis is an analytical method of chemistry and molecular biology, um separate different types of molecules. It wanders a mixture of molecules to be separated under influence an electric field by a polymer which is in an ionic Buffer solution is. Depending on the size and Charge of the molecules move them differently quickly through the molecular sieve acting polymer. Small, negatively charged molecules are the fastest in the direction of positively charged anode and positively charged molecules in Direction of the negatively charged cathode.

EP 1,447,134 A1 discloses a microfluidic system of the assignee Agilent Technologies, Inc., in which a sample to be analyzed is guided along a channel in a microfluidic chip under the influence of, for example, electrical forces.

EPIPHANY

It The object of the invention is a powerful chip for Handle a fluid provide. The task is done by of the independent claims. Further Embodiments are in the dependent claims shown.

According to one exemplary embodiment of the present invention is a chip for handling a fluid created, wherein the chip a Substrate, a plurality of arranged in and / or on the substrate Wells for receiving the fluid and at least one channel in and / or on the substrate to form a fluid connection between the wells having all wells in fluid communication along are arranged exactly one common direction.

According to one Another exemplary embodiment is a method for handling a fluid, wherein in the method Fluid in a plurality of arranged in and / or on a substrate Wells is absorbed and the fluid between the plurality of wells moved through at least one channel in and / or on the substrate which forms a fluid connection between the wells, wherein all fluidly connected wells along exactly one common direction are arranged.

According to Another exemplary embodiment is a A chip for handling a fluid provided, wherein the chip is a substrate, a plurality of groups of in and / or disposed on the substrate Wells for receiving the fluid and at least one channel in and / or on the substrate for each of the groups to form one Having fluid communication between the wells of a respective group, each of the groups being managed separately from the other groups a separate fluid is operable.

According to one Another exemplary embodiment is a method for handling a fluid, wherein in the method Fluid in a selected group of a plurality of Groups of wells arranged in and / or on a substrate recorded is the fluid between the plurality of wells of the selected Group through at least one channel in and / or on the substrate the selected group is moved, which at least a channel provides fluid communication between the wells of a respective group forms, and the selected group separately from the others Groups is operated to handle the fluid.

According to Another exemplary embodiment is a Measuring device provided for handling a fluid, wherein the meter a chip receiving device for recording a chip with the features described above and a processing unit for processing a fluid in the chip when the chip recorded in the chip receiving device.

According to one first aspect of the invention, independent or common can be realized with a second aspect of the invention, a microfluidic chip is provided in which a plurality Wells or fluid receiving wells with each other in Fluid communication stand and lined all wells in a linear manner are. In this way, an entire surface of a substrate can ideally exploited to the length of a separation channel to maximize between some of the wells. This is for a separation device, such as an electrophoretic Separator, extremely beneficial.

According to a second aspect of the invention, which may be implemented independently or in common with the first aspect of the invention, there are provided on a substrate a plurality of independently operable corrugated groups, each in fluid communication with each other through channels. By using a single substrate to provide multiple different microfluidic test wells with interconnect structures, the area of a substrate, such as a Glass chips, to be used optimally.

Especially It is advantageous to have a plurality on one and the same substrate each operable separately along a linear direction Well groups provide, because then both a long separation channel as also an ideal use of an available Substrate surface is possible.

Consequently can according to the invention a chip layout for Multi-use chips are created with long separation channels.

Conventional chip production costs are proportional to the area the glass content on the chip. Be longer separation distances With a linear separation channel needed, the chip area needs be enlarged accordingly, if a square Well format, for example, a 4 × 4 well format, maintained shall be.

According to the invention, to stay with the above example, a 4 × 4 well to four independent 1 × 16 Wellgrids be converted. These four separate chip areas can each be independent operated by each other. In this example, the chip is used 4 × and only differently positioned in the device, to each operate a single 1 × 16 section. By the elongated arrangement is obtained for example to 4 to 5 times linearly extended separation distance. The glass area is thus a total of four times the 4 × 4 arrangement. However, since the chip uses 4 × can be the total manufacturing cost per chip unit be analogous to the 4 × 4 grid. Constant production costs can thus be guaranteed, although the separation channels advantageously gain in length.

One Such device can be used as a glass chip for insertion into a device for the automatic performance of electrophoresis (for Example gel electrophoresis) can be used. Therefor gets on a chip with the wells and the connection channels previously stuck to a plastic bracket, among other things also larger fluid reservoirs for Filling the Wells provides. In this will be subsequently Electrodes immersed to generate an electric separation field. To have a higher resolution in electrophoresis To achieve, among other things, is usually a longer one Separation distance required (for example, for sequencing or genotyping by capillary electrophoresis). For example For example, a separation path of 5 cm to 7 cm may be advantageous. Furthermore is according to the invention a substantially linear Flow path of the samples during separation advantageous, otherwise there is a curve lubrication of the separated along the separation path Fractions of the sample could be made.

According to the invention now a separate line of wells and channels each independently be provided usable. Alternatively, a respective column of matrix-like wells and associated separation channels each independently usable. The measuring device can be adapted to this changed geometry of the biochip in particular by adapting the electrode geometry to it becomes. For example, when switching a 4 × 4 Grids on four 1 × 16 grids 16 linearly arranged electrodes be provided, which by means of a displacement device respectively into a series of wells that communicate with each other via separation channels are connected, can be immersed.

Therefore For example, a chip can be provided in which all the fluid-communicating Wells are arranged along a common direction. An inventive Chip can be operated separately with a plurality (ie provided outside fluid communication) areas each of which has a separate separation channel and other channels may have.

in the Further, additional embodiments of the chip according to both Aspects described. These configurations also apply to the procedures and for the meter.

At least one of the at least one channel may be along the common direction be arranged running. This channel can be the actual separation channel along which one electric field is applied to different ones Separate fractions of the sample.

At least one of the at least one channel may be substantially along the total extent of all fluidly connected wells extend. This provides a sufficiently long separation channel, to a high resolution in the separation of a multi-component sample to reach.

It may be at least one more plurality of in and / or on the substrate arranged further wells for receiving a further fluid provided be. Furthermore, at least one further channel in and / or on the substrate to form a fluid connection between the others Wells be provided. All others in fluid communication Wells can be arranged along the common direction be. This allows different types of wells to be formed For example, wells for taking different samples, wells for mixing or storing samples and waste containers.

A plurality of groups of wells disposed in and / or on the substrate for receiving Menus of the fluid may also be provided to the chip. Moreover, at least one channel may be provided in and / or on the substrate for each of the groups for establishing fluid communication between the wells of a respective group. Each of the groups may be operable separately from the other groups for handling a separate fluid. In this way, a plurality of wells can be coupled together and functionally decoupled from other groups of wells. For example, the separation channels of different groups of wells may be formed parallel to each other. With this geometry, each of the plurality of fluidly communicating wells can be used as a separate device for performing a biochemical assay.

Especially For example, the chip may be sixteen, more particularly exactly sixteen, in fluid communication standing wells along the exactly one common direction. This geometry is with Applicant's Bioanalyzer System Agilent Technologies very well tolerated. With such geometry can a sample first on an injection cross to a defined position, then along a separation channel to be exposed to an electric field, under the influence of which different components of the sample according to their electrophoretic Mobility separated and attached to a detector at one end the linear well arrangement can be detected.

The Wells can be arranged as a matrix in and / or on the substrate and each group form a row or column of the matrix. each Row or column of the matrix may be separate from the other rows or columns of the matrix.

In all groups can all wells within a respective Group can be arranged along exactly one common direction. This has advantages when immersing electrodes an electric field is applied to the wells of a group intended to initiate an electrophoretic separation. Then can a linear array of electrodes just vertical to the array the well groups are shifted, and by vertical lowering immersed in the wells of each group in fluids in the wells so as to apply an electric field to the fluids in the wells.

All Wells of all groups can go along exactly one common Direction can be arranged. In other words, a Connection axis of the wells of each group parallel to each connection axis to be from other groups.

On The chip can have four, in particular exactly four, groups be provided by Wells. This allows for a sufficient small sizing sufficient mechanical stability of the Substrate that (for example, providing 16 wells per group) too small a number of groups to a long thin one Glass rod could lead to which Fragility could tend. It turned out that when providing several groups, for example of at least four groups, a good mechanical stability of the chip can be achieved.

Wells different groups can share with each other Fluid communication (i.e., not in fluid communication with each other be brought), and therefore functionally decoupled.

The Substrate may be, for example, glass, plastic, metal, ceramic and / or comprise a semiconductor material. It is with these materials possible using simple processing methods, channels etch into the substrate, which then the fluid connection between the individual wells. On such a substrate Then a plastic holder can be placed on the Make the wells has openings. This can be used as a caddy be designated. Over the openings in the Caddy can a fluid is introduced into the respective wells. It is also possible in an automatic separator, Electrodes through the holes in the caddy into the Wells introduce.

The Wells may be formed as trenches in the substrate be. This allows easy processing of the wells, for example by means of etching techniques.

When Caddy can provide an attachment for placement on the substrate be, wherein the attachment a plurality of filling reservoirs may have, each of which corresponds to an associated the wells can be configured.

The Substrate may be formed of two bonded sub-substrates, so that between the sub-substrates of the channel is formed or the channels are formed and so that the wells at least partially formed in one of the two sub-substrates. through interconnecting two (for example glass) substrates and the processing of the two substrates in a suitable manner for example, wells in an upper substrate and channels are formed in a surface area of the lower substrate, wherein by means of placing the two sub-substrates on each other Wells are brought into fluid communication with the channels can. This represents a particularly protected Arrangement of the channels, in which a microfluidic Sample during the separation process not the surface is exposed.

At least one of the channels can be a separator channel, in particular an electrophoretic separation channel. However, other separation methods or biochemical analysis methods are possible with a chip according to the invention.

At least two of the channels can cross each other, so that an injection cross can be formed, by means of which a sample guided in a defined manner by the arrangement of channels can be.

in the Further embodiments of the measuring device will be described, which also apply to the chip and the method.

The Processing unit of the measuring device can be a plurality of electrodes, each of which is for immersion in an associated the wells can be arranged when the chip in the chip receiving device is included. In this respect, the electrode arrangement of the processing unit be adapted to the well arrangement of the chip.

The Processing unit may include a plurality of movable electrodes have to be immersed in an associated group of Wells are movable when the chip in the chip receiving device is included. For example, the processing unit may be the Scan groups of wells line by line or column by column, one at a time activated group of wells exposed to an electric field. This ensures that not for each (possibly unused) well of a multi-group array of wells a separate Electrode must be provided.

The Meter can be used to separate at least two components a fluid or used as a microfluidic measuring device be. So it can be beneficial in the life science field, one to separate biological samples with multiple protein or gene components, what according to the method of gel electrophoresis due to the different ratio of charge and mass of different fractions of particles is. For this purpose, the invention Sample filled in one of the wells, after a certain Mechanism passed through a plurality of wells, and after passing through a separation channel under the action of an electrical Feldes determined by a detector, which fractions in the separated sample are included.

BRIEF DESCRIPTION OF THE FIGURES

Other Objectives and many of the attendant advantages of embodiments The present invention will be readily apparent and be better understood with reference to the following more detailed description of embodiments in Related to the attached drawings. Characteristics, which are essentially or functionally the same or similar are provided with the same reference numerals.

1 shows an electrophoresis chip according to an exemplary embodiment of the invention.

2 shows an enlarged view of a well of an electrophoresis chip in a measuring device according to an exemplary embodiment of the invention.

The Representation in the drawing is schematic.

1 shows a biochip 102 for handling a fluidic sample (not shown) according to an exemplary embodiment of the invention.

The biochip 100 contains a glass substrate 102 in which a plurality of wells 104 are formed in a matrix. According to the embodiment of 1 contains the matrix of wells 104 16 columns and four rows. Each of the wells 104 is adapted to receive a fluidic sample or a solvent. The different wells 104 are by means of several separation channels 106 fluidly connected to each other, wherein the separation channels 106 in a surface of the substrate 102 are etched.

As in 1 shown are the wells 104 in four groups 110 . 112 . 114 . 116 split, which are each in fluid communication, but which are separately operable, so that only the wells 104 a respective group 110 . 112 . 114 . 116 to carry out a joint analysis. Wells 104 different groups 110 . 112 . 114 . 116 On the other hand, they are except fluid communication and can not be functionally coupled.

As in 1 further shown are all wells 104 that of a particular group 110 . 112 . 114 . 116 are all assigned along exactly one common direction, namely in accordance with 1 horizontal direction, arranged.

The longest of the channels 106 of each group 110 . 112 . 114 . 116 is a so-called separation channel 108 , Along the separation channel 108 A separation of components of a microfluidic sample takes place in one of the wells 104 is filled, as described in more detail below. The separation channel 108 also runs essentially in the horizontal direction according to 1 and connects most of the wells 104 a respective group 110 . 112 . 114 . 116 , By the separation channel 108 in the We along the entire length of all fluidly connected wells 104 a respective group 110 . 112 . 114 . 116 extends, a sufficiently long separation distance is possible.

In the embodiment according to 1 are per group 110 . 112 . 114 . 116 exactly 16 wells 104 provided over the channels 106 are in fluid communication with each other and are lined up horizontally.

Each of the groups 110 . 112 . 114 . 116 can be used for a separate biochemical analysis. The Wells 104 are as trenches in the glass substrate 102 educated. As 1 it is also apparent in each of the groups 110 . 112 . 114 . 116 a so-called injection cross 118 provided as a "hub" for passing fluidic samples through the wells 104 and channels 106 according to a predetermined schedule.

In a detection area 122 can make a fluidic sample after this some of the potty 104 as well as some of the channels 106 has passed through in a predeterminable order, fractionally separated detected by means of an optical detection method.

For example, to separate a sample, one may initially be from a potty 124 in a potty 126 and then into a potty 128 be transferred before the sample starting from the well 128 along the separation channel 108 is separated by means of an electrophoretic force, then in the detection area 122 to be detected.

To apply an electrophoretic force to the sample prepared according to 1 along the separation channel 108 migrated from far left to far right, becomes a group first 110 . 112 . 114 . 116 from Wells 104 selected to be used for an experiment. Then an electrode assembly 130 an electrophoretic measuring device (for example similar to a bioanalyzer of the assignee Agilent Technologies) initially so moved (see reference numerals 132 ) that the corresponding electrode pins 134 above the wells 104 the selected group 110 . 112 . 114 . 116 are located. Then the electrode assembly 130 lowered to the Wells 104 and immerse the liquids contained therein, and it is applied by applying an electrical signal to the electrodes 134 an electric separation field along the separation channel 108 created.

2 shows an enlarged view of a chip 210 in a measuring device 200 according to an exemplary embodiment of the invention.

In the arrangement off 2 is a first glass substrate 102 provided in which the wells 104 are formed as through holes. These are by means of the electrophoretic separation channel 108 connected to each other, which, however, in a second glass substrate 202 is formed, which with the first glass substrate 102 is bonded. A plastic caddy 204 can be placed on this arrangement. Then, a fluidic sample 206 by means of a pipetting device (not shown) in one with an arrow 208 indicated way into the well 104 be introduced.

It It should be noted that the term "exhibit" does not excludes other elements and that the "one" does not exclude a plurality. Also, elements, in connection with different embodiments are described combined. It should also be noted the reference numerals in the claims are not considered the scope of protection to be interpreted as limiting the claims.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• EP 1447134 A1 [0003]

Claims (28)

Chip for handling a fluid, said chip having a substrate; a plurality of in and / or on the well arranged in the substrate for receiving the fluid; at least a channel in and / or on the substrate to form a fluid connection between the wells; all being in fluid communication Wells are arranged along exactly one common direction. The chip of claim 1, wherein at least one of the at least a channel arranged along the common direction running is. The chip of claim 1 or 2, wherein at least one the at least one channel extends substantially along the entire Extension of all fluidly connected wells extends. The chip of any one of claims 1 to 3, further comprising: a further plurality of arranged in and / or on the substrate further Wells for receiving another fluid; at least one another channel in and / or on the substrate to form a fluid connection between the other wells; all being in fluid communication standing further wells along the common direction are. The chip of any one of claims 1 to 4, further comprising: a Plurality of groups of in and / or disposed on the substrate Wells for receiving the fluid; at least one channel in and / or on the substrate for each of the groups to form one Fluid communication between the wells of a respective group, in which each of the groups separately from the other groups to manage one separate fluid is operable. A chip according to any one of claims 1 to 5, wherein sixteen, in particular exactly sixteen fluidly connected wells along which are arranged in exactly one common direction. A chip for handling a fluid, the chip having one substrate; a plurality of groups of in and / or on the substrate arranged wells for receiving the fluid; at least one Channel in and / or on the substrate for each of the groups for forming a fluid connection between the wells of a respective one Group, each of the groups being separate from the other groups operable to handle a separate fluid. A chip according to claim 7, wherein the wells are in the form of a matrix are arranged in and / or on the substrate and each group one Forming a row or a column of the matrix. The chip of claim 7 or 8, wherein all wells of one Group are arranged along exactly one common direction. A chip according to any one of claims 7 to 9, wherein all wells of all groups along exactly one common direction are arranged. Chip according to one of claims 7 to 10, wherein four, in particular exactly four, groups of wells provided are. Chip according to one of claims 7 to 11, wherein at least one of the groups has sixteen wells, in particular exactly sixteen wells. Chip according to one of claims 7 to 12, where wells of different groups are out of fluid communication standing together. Chip according to one of claims 1 to 13, wherein the substrate comprises a material from the group formed is made of glass, plastic, metal, ceramics and semiconductor material. Chip according to one of claims 1 to 14, wherein the wells are formed as trenches in the substrate. Chip according to one of claims 1 to 15, comprising an attachment for placing on the substrate, wherein the Attachment has a plurality of filler neck, from each corresponding to an associated one of the wells is configured. Chip according to one of claims 1 to 16, wherein the substrate is formed of two bonded sub-substrates, so that between the sub-substrates of the channel is formed or the channels are formed and so that the wells at least partially formed in one of the two sub-substrates. Chip according to one of claims 1 to 17, wherein at least one of the channels is a separation channel, in particular an electrophoretic separation channel. Chip according to one of claims 1 to 18, wherein at least two of the channels intersect each other so that an injection cross is formed. Measuring device for handling a fluid, wherein the meter has a chip receiving device for receiving a chip according to one of claims 1 to 19; a processing unit for processing a fluid in the chip when the chip is received in the chip receiving device is. A meter according to claim 20, comprising Chips according to one of claims 1 to 19, in the chip receiving device recorded or receivable. Measuring device according to claim 20 or 21, wherein the Processing unit comprises a plurality of electrodes, of each one for immersion in an associated one of the wells is arranged when the chip is received in the chip receiving device. Measuring device according to claim 20 or 21, wherein the Processing unit has a plurality of movable electrodes, for immersing in an associated group of wells are movable when the chip is received in the chip receiving device is. Measuring device according to one of the claims 20 to 23, arranged for separating at least two components of the fluid. Measuring device according to one of the claims 20 to 24, set up as a microfluidic measuring device. Measuring device according to one of the claims 20 to 25, set up as a measuring device from the group from a life science device, an electrophoresis device, a gel electrophoresis apparatus, a liquid chromatography apparatus and an HPLC. A method of handling a fluid, wherein the Method has Picking up the fluid in a plurality of in and / or on a substrate arranged wells; Move the fluid between the plurality of wells through at least one Channel in and / or on the substrate, which has a fluid connection between the Wells forms; wherein all fluidly connected wells are arranged along exactly one common direction. A method of handling a fluid, wherein the Method has Picking up the fluid in a selected one Group of a plurality of groups of in and / or on one Substrate arranged wells; Moving the fluid between the Plurality of wells of the selected group by at least one Channel in and / or on the substrate of the selected group, which at least one channel is a fluid connection between the Forms wells of a respective group, Operate the selected Group separately from the other groups to handle the fluid.