WO2008128745A1

WO2008128745A1 - Device and method for the controlled transport of microfluid samples

Info

Publication number: WO2008128745A1
Application number: PCT/EP2008/003188
Authority: WO
Inventors: Thomas Van Den Boom; Bedrich Hosticka; Hoc Khiem Trieu
Original assignee: Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.
Priority date: 2007-04-20
Filing date: 2008-04-21
Publication date: 2008-10-30
Also published as: DE102007018752A1; DE102007018752B4

Abstract

A device for transporting a microfluid sample (110) comprises a substrate (12), a channel (130) formed in the substrate (120), a first electrode (141), a second electrode (142), a sensor (151) and a controller (160). The sensor (151) is located along the channel (130) between the first electrode (141) and the second electrode (142) and is designed to perform a measurement regarding the microfluid sample (110). The controller (160) controls a voltage between the first electrode (141) and the second electrode (142) as a function of a result of the measurement. The first electrode (141) and the second electrode (142) are located at different positions along the channel (130), in such a manner that an electric field can be generated by the voltage between the first and second electrodes (141, 142) along the channel (130) from the first electrode (141) to the second electrode (142).

Description

Apparatus and method for controlled transport of microfluidic samples

description

The present invention relates to an apparatus and a method for the transport of microfluidic samples, and in particular to a speed and temperature control of an electrohydrodynamic flow for the transport of microfluidic samples, for example on a lab-on-a-chip.

Biochips play an important economic role today and are among the technological achievements of recent times. The interest in biochips is based in particular on the possibility of an extraordinary interdisciplinarity, for example between microelectronics, micromechanics, nanotechnology and modern life sciences. One class of biochips includes the so-called lab-on-a-chip (LOC) systems, which include microscale devices suitable for various types of chemical and cellular analyzes. The LOCs may be classified as microfluidics based on a network of microchannels, or as a microarray, for example similar to a microtitre perforated plate-like format. A third type of LOCs uses micromechanical structures as a microreactor for chemical synthesis.

A driving force for LOCs has been the need for combinatorial chemistry to make drug development cheaper and faster, as in Frost and Sullivan, for example. "Lab-on-A-Chip: The Revolution in Portable Instrumentation - 4 ^th Edition ", 2002, D229, with miniaturization as the first step, using a microarray capable of simultaneously examining a large number of different specimens at the same time " provide. However, the biologists are also concerned with the question of how different molecules or cells can be moved, separated, mixed with others and the results can be visualized. A goal of the entire general LOC development is thus a so-called micro-total-analysis-system (μ-TAS), which combines all laboratory functions from the sample mixture via reaction chamber and transport to a detection of the final product. One answer to this development is microfluidics.

Non-array-based LOCs generally process liquids that, for example, flow from one location on the analyzer (or synthesizer) to another location. Microfluidic devices have, for example, pumps, valves and channels and can be designed as a glass or plastic chip. The chips may use either elective or combination pressure, electrorosmosis, electrowetting, electrophoresis, or other means (capillary force, for example) to move samples through a network of microscopic channels and containers. So far, however, the degree of integration is not yet very high and there is an urgent need to further improve this.

A major problem remains liquid transport on the chip. The micromechanical pump systems available today quickly become confusing, for example due to a large number of hoses and valves. Tilen, are usually very susceptible to leaks and their production is usually very expensive. Simpler would be so-called dynamic micropumps, in which a direct energy conversion takes place in liquid movement. These include, for example, electrohydrodynamic or magnetohydrodynamic pumps that are easy to manufacture, but in their properties are dependent on the liquids to be transported. Successes have recently been achieved with electro-osmotic pumps. They are based on electroosmosis, which is a macroscopic phenomenon that results from an electric double layer caused by ions in the liquid and by surface electric charges in the capillary walls. When an electric field is applied between two electrodes, the liquid flows from one electrode to the other, with the cations moving to the cathode, moving (or tearing) the liquid with it.

Problems of existing electroosmotic systems are on the one hand the control of the flow, which depends on a multitude of parameters, as well as the control of the temperature, which in turn depends on the applied field and thus on the flow. Under unfavorable circumstances, the sample liquid, which comprises, for example, only micro- or picoliters, can either evaporate considerably or even evaporate completely.

In summary, in today's microfluidic systems for conveying liquids in microchannels, metering pumps or micromechanically produced micropumps are used. Micropumps are particularly attractive because they counteract miniaturization and the high degree of system integration. men. Typically, however, mechanical micropumps have valves and one or more diaphragms driven piezoelectrically, electrically or thermopneumatically. Such micropumps are known, but are disadvantageous in terms of high cost and reliability issues. On the other hand, non-mechanical micropumps are being studied in, for example, Daniel J. Lasers: "Desing, Fabrica- tion, and Application and Silicon Electroosmotic Micropumps," Dissertation, Stanford University, June 2005.

Electro-osmotic pumps or electrowetting are of particular interest because they can be applied to all liquids that have ions or polarizable molecules. Known examinations are limited as far as possible to the realization of micropumps, and aspects such as flow monitoring or control systems, as well as issues relating to system integration, remain largely unconsidered. However, answers to these questions are essential for the realization of LOC systems. Known analyzers use electrophoresis to separate particles or particles, and electroosmosis occurs only as a by-product. Electro-osmosis phenomena and their applications within an LOC are currently hardly used economically. Publications can be found in: Todd M. Squires, Martin Z. Bazant: "Induced-charge electro-osmosis"; Journal of Fluid Mechanics, 2004, vol. 509, pp. 217 - 252); Gonzalez, A. Ramos, A. Castellanos, "Pumping Liquids Using Traveling Wave Electro-Osmosis: A Nonlinear Analysis," Proc. 2005 IEEE International Conference on Dielectric Liquids, pp. 221 - 224; Martin Z. Bazant, Todd M. Squires, "Induced Charge Electrokinetic Phenomena: Theory and Microfluidic Applications"; Physical Review Letters, volume 92, number 6, 2004; Jie Wu, "Biased AC Electro-Osmosis for On-Chip Bioparticle Processing, IEEE Transactions on Nanotechnolgy, vo 5, no.2, Maren 2006; DJ Laser, JG Santiago, "A review of micropumps"; Journal of Micromechanics and Microengineering, VoI 14, 2004, R35 - R64; Peter Woias, "Mi- cropumps - past, progress and future prospects", Sensors and Actuators B 105, 2005, pp 28-38; Frost and Sullivan: "Lab on a Chip - Advances on Microfluidics"; 2004, D323 and the above-mentioned reference by DJ Laser Further details on electrowetting can be found in: Frieder Mugele, Jean-Christophe Baret, "Electrowetting: from basics to application" , Journal of Physics: Condensed Matter 17 (2005) R705 - R774.

Based on this prior art, the present invention has the object to provide a device and a method for transporting microfluidic samples, which in particular allows a speed and temperature-controlled electrohydrodynamic flow.

This object is achieved by a device according to claim 1 in a method according to claim 28 or claim 29.

The core idea of the present invention is that a device for the controlled transport of microfluidic samples by means of electrohydrodynamic flow, such as by means of electro-osmotic flow (EOF), can be created by forming at least one capillary or channel within a substrate Different positions have a first and second electrode. The first and second electrodes as well as the capillaries are designed such that when a voltage is applied to the first and second electrodes, an electric field is formed along the capillary, so that the microfluidic sample differs from the positive electrode. tion of the first electrode moves to the position of the second electrode.

Furthermore, the device has at least one sensor, which detects a movement of the microfluidic sample and thus allows a control of the transport or the expansion of the microfluidic sample. By way of example, the sensor can be a photosensor which, for example, enables time recording in which the microfluidic sample passes the photosensor. By means of further photosensors, a speed detection of the microfluidic samples can thus also take place through the capillary or a determination of the volume of the microfluidic sample can be made by detecting a start and an end of a microfluidic sample (since a diameter of the capillary is known). It is also possible that the photosensors are part of a photo line or multiple photo lines are used for motion detection.

Further, in other embodiments, the device may include a temperature sensor that allows temperature sensing of the microfluidic samples. In addition, the device for transport can have a biosensor which, for example, allows an examination of contents substances or bio-chemical properties of the microfluidic sample.

In further embodiments, the capillary is arranged in a meandering manner and has additional electrodes, so that one or more microfluidic samples can move along the meandering structure. The substrate may, for example, comprise glass or another transparent medium and may be provided with a circuit, Control, regulation or regulating device may be connected, for example, on a substrate substrate (eg, a semiconductor substrate with a CMOS structure), on which the substrate is disposed. In this way, multiple channels on a chip with a few electrodes can be easily controlled, eliminating many mechanical parts, such as would be required in the electromechanical pumps described above.

By means of a variable voltage regulation of the different electrodes, it is also possible to influence the speed of the microfluidic samples or, if several electrodes are present, to influence different microfluidic samples separately. For example, a speed of a single (microfluidic) sample in a series of microfluidic samples can be regulated in their speed so that a minimum distance between two successive microfluidic samples is formed. The capillary may have on its walls a coating, for example of a hydrophilic materials (polymers) or also have a covalent coating. A thermocouple can also be used to adjust the temperature and, moreover, it can be advantageous to influence the speed of the microfluidic samples by adding wetting agents or organic modifiers.

The present invention utilizes electrohydrodynamics and differs from heretofore commercially used systems based on electrophoresis in which electroosmosis occurred only as a concomitant phenomenon. However, it is possible to choose the channel geometry such that the electro-osmosis provides a very effective transport mechanism. offers. Thus, the geometry of the channels / capillary can be designed in such a way that the osmosis (or electroosmosis) is effectively supported and the electrophoresis has only a secondary effect. This clears the way for mass transfer without mechanical parts.

In further embodiments of the invention, electrowetting as a driving electrohydrodynamic force are provided in addition to the electroosmotic flow. For electrowetting, there are no capillaries; instead structured and functionalized surfaces can be used. Depending on the principle, several electrodes can be used for this purpose - for example, additional electrodes "from above." The number of electrodes and the arrangement can be selected according to the requirements or wishes.The regulation of the electrodes can be based on the same principle as with the EOF In addition, electrodes for surface functionalization may be provided in this exemplary embodiment, as a result of which, for example, surface properties (wetting, surface adhesion, friction, etc.) may be changed by potential differences between electrode pairs and for regulatory purposes.

Unlike in the embodiment described above, the meandering path for the sample samples can be dispensed with here, but instead a kind of decision tree which is operated via the measurement results from the biosensors and thus via the control. Thus, the path or path of a sample can be chosen as a function of the measurement result on one of the biosensors and is not predetermined. This has the advantage that, for example, an optimized number of measurements can be carried out for a particular sample, and unnecessary measurements can be avoided. As in the embodiments described above, the photosensors are the basis of cruise control. The temperature control can be done in the same way.

A basic structure of an analysis system with a microfluidic and an electro-osmotic flow (EOF) has, for example, a glass chip with the channels / capillaries and electrodes and can for example be mounted on a silicon chip. The silicon chip may comprise the sensor, actuators and other electronics, with both chips (the glass chip and the silicon chip) being able to form a sandwich structure.

The capillaries, which are incorporated in the exemplary glass chip, serve to transport the sample liquids by means of electroosmosis. The driving force are electrode pairs whose voltage drop drives the fluidics. The electrodes can be selectively and separately controlled, the drive being controlled by an electronic, e.g. on the underlying exemplary silicon chip may be integrated takes place. For this purpose, for example, plated-through holes can be made, and the silicon chip can have, for example, the complete electronics, wherein it is advantageous to place the blocks and in particular the sensors and actuators in such a way that they are matched with the position of the capillary.

In particular, the following components may be included in the electronics:

1. The part of the sensor which is responsible for the speed and temperature control and which may have photosensors and temperature sensors.

2. Sensor signal processing (preferably noise-reduced) for signal conditioning of the photo and temperature sensors. 3. The Aktorik, which may be formed for example by pairs of electrodes and a temperature controller and is used to control the entire system.

4. A user interface that allows programming of setpoints for a control and that can further provide a potential display driver for visualizing data.

5. An analog circuit part that references to

Provides available, digitized signals and controls the actuators.

6. A microcontroller that controls the entire process.

7. The actual useful part for a bioanalysis of the sample with sensors, sensor signal processing, etc.

In addition, if it is desirable for the specific application, further elements can be integrated into the electronics.

The basic system described so far can have two control loops:

a) a speed excitation and b) a temperature control.

The speed control can be done as follows. The velocity v of the electroosmotic flow corresponds to:

v = μ _E0F • E =? - $ ^■ • E, (1) η where ε is the dielectric constant, ζ is the zeta potential and η is the viscosity and E is the electric field strength that forms when voltage is applied to the electrodes along the capillary. Thus, the amplitude of the electric field can easily control the speed of the e-osmotic flow, and the speed can be detected by means of the photosensors. The photosensors, which are placed below the exemplary transparent glass capillaries, for example, can determine the speed of the individual sample sam- ples in each channel or also in each channel section. In this case, at least two photosensors can be placed per measuring section and the speed can be determined with the aid of image processing electronics (eg using CMOS technology) from a differential calculation - for example from a time difference, which requires a sample sample to overcome the distance between two photosensors. The two photosensors can also be part of a photosensor line. Subsequently, a comparison can be made between actual values thus obtained and setpoint values set by the user. By specifying the target values, the user can, for example, react to insufficient results from the bioanalysis of the useful sensors (biosensors). This is the case, for example, if the sample passes too fast or the biosensors so that the analysis can not be done in the required quality. On the other hand, however, the throughput can be increased and thus the most efficient use of the plant can be achieved. If several samples flow through the channel, or several channels are on the glass chip, which may also intersect, can also intervene regulating and coordinating on the control of the respective pairs of electrodes.

After the target / actual comparison, the controlled variables are determined and, for example, via a DAC (digital-analogue Converter) of the actuator and thus the electrode drive. In this case, for example, via the amplitude, the electric field and thus the speed of the e-lektroosmotic flow for each micro-channel (section) is set.

A second control circuit comprises a temperature control, which is desirable in particular for two reasons. The most important reason results from a risk of evaporation or evaporation of the sample samples, which is particularly given because their volume can only be microliters or picoliters that are drawn between two electrodes with a relatively high voltage. Another reason for a temperature control results from the influence of the temperature on the viscosity of the sample and thus directly on the speed of the electro-osmotic flow. The dependence of the viscosity on the temperature is expressed by the following equation.

η = H ₀ ^• e ^RT , (2)

where E _{A is} an activation energy, R is the general gas constant and T is the absolute temperature. In addition, the zeta potential also depends on the temperature, but not as much as the viscosity, which depends exponentially on the temperature; instead, the zeta potential shows a potential dependence ratio:

Thus, also by the zeta potential, a dependence of the speed of the temperature is given.

An approach to temperature control can be described as follows. Per channel / capillary or channel section, a temperature sensor or the transparent capillary, for example, placed on the silicon chip. So that can the temperature can be measured directly. However, since the safety over the actual absolute temperature can be relatively small, a measure of the evaporation can be derived from the measurement of the decrease in the geometric sample expansion via the photosensors previously used for the speed. Since the sample samples pull relatively slowly through the capillary, their extent can be detected with sufficient accuracy. As the expansion shrinks, it is highly likely to cause liquid loss through evaporation. If the liquid sample (sample sample) changes in its longitudinal extent as a result of a temperature decrease (or a temperature increase) according to its thermal expansion coefficient p, this can be detected directly by the temperature measurement and other reasons can be ruled out. Thus, it is possible to react to the risk of evaporation directly via the temperature control. Similar to the speed control, the user can again intervene here and specify desired values, for example, a temperature change if such desired values are violated

(an increase or decrease). Indirectly, the user also takes on the temperature setting

Change in the electroosmotic flow velocity in

Purchase, which, however, can be adjusted again, for example via the voltage. Similar to the speed control, changes can also be made individually by channel during temperature control. The controlled variable from the nominal-actual comparison is fed via a DAC to the control electronics for the respective thermocouple. This also closes this loop.

In addition to the aforementioned possibilities of influencing the electroosmotic flow, there are other variables or parameters which influence the electroosmotic flow and can accordingly be exploited according to embodiments. For example, the electro-osmotic flow drops at a low pH (buffer pH), as this changes the charge or structure of the sample. can be changed. Likewise, higher ion concentration or buffer concentration reduces zeta potential and electroosmotic flow (high currents and heat, sample attachment). The zeta potential can also be influenced by so-called organic modifiers. The electro-osmotic flow can be increased, for example, by adding wetting agent, which attaches itself to the capillary walls via hydrophobic and / or ionic interactions (anionic wetting agents increase the EOF). On the other hand, neutral electrophilic polymers reduce electroosmotic flow by shielding surface charges and result in increased viscosity. There are also deposits on capillary walls via hydrophobic interactions. Finally, covalent coatings (chemical bonding on capillary walls) can also influence the electroosmotic flow. However, there are stability problems with the many possibilities. The above-mentioned possibilities of influence are thus based on adding additives to the samples or treating the capillary walls, for example, with nanotechnological methods on the surface. The latter methods are more static, the former quite dynamic to handle.

Embodiments of the present invention relate to a variety of technical applications, of which only a few should be mentioned here. On the one hand it concerns the analytical equipment in the health service - directly at the sickbed, in the emergency room, in the Ambulanzwagen, veterinary medicine, point-of-care, in the war also on the battlefield. Another area of application includes, for example, an environmental analysis, sampling of soil, water, air or monitoring purposes on the car or on pipelines. Likewise, applications in food, chemical, pharmaceutical, cosmetics or biotech production lines are possible. Further fields of application are offered in the laboratory; either in the process / development or during experimental chemical or biochemical transformations.

Since control of a system requires control thereof, the speed and temperature control of mass transfer in microfluidics in accordance with embodiments of the present invention is advantageous in many respects and thus differs fundamentally from previously known systems. This includes, for example, the multi-sample functionality, which allows the velocity control to simultaneously determine the location of the sample or multiple samples within the microfluidics. Simple electronic logic allows multiple samples to be routed simultaneously through the network of freely configurable electrode arrays / decision trees (as long as the different samples are in different locations), and a collision can be eliminated thanks to monitoring and separate control.

Because electroosmotic flow is controlled in accordance with embodiments of the present invention, microfluidic systems become more flexible, much more usable, and less expensive, making them more attractive for economic use. Embodiments thus also allow a programming option by a user, which is only extremely limited possible in conventional systems. Problems such as the evaporation or, in the worst case, the evaporation of a sample, thus largely disappear in the exemplary embodiments of the present invention.

Furthermore, embodiments have a simple and clear handling, as by an exclusive Use of electrohydrodynamics as mass transport mechanism Mechanical pumps and inflows from the outside are eliminated. This makes the external structure very clear and the system is much easier to handle - for example, countless hose connections are eliminated. Another advantage of embodiments is given by the fact that a few mechanical parts at the same time imply low maintenance. The elimination of the mechanical parts eliminates the need for regular maintenance and inspection of the hoses, pumps, valves, etc. Replacement of wear parts can be avoided and thus no longer need to know about the connection of the mechanical parts and the flow control via external components , Thus, the training time and the dead time (waiting time) for these systems are significantly reduced and the range of use increases at the same time.

As already mentioned, it is advantageous that evaporation or evaporation can be avoided to the greatest possible extent, since constant monitoring and control of the temperature can be used in good time for any critical operating conditions. The regulation makes it possible that several samples can circulate and the amount of sample can be further reduced due to the system. Furthermore, constant monitoring and control can also be advantageous in terms of achievable stability, since a stable microfluidic flow is made possible. Thus, the throughput can also be increased. Finally, embodiments allow a fast, accurate and more cost-effective sample analysis, since a control allows a speed-optimized sample throughput via the electro-osmotic flow. Since several samples can be passed through the system at the same time, the throughput can be considerably increased and the costs are reduced. Cost-reducing also affects the fact that according to embodiments expensive mechanical parts are eliminated and thus also expensive mechanical spare parts.

Preferred embodiments of the present invention will be explained in more detail below with reference to the accompanying drawings. Show it:

1 shows a device for transporting a sample within a capillary according to an embodiment of the present invention;

Fig. 2 is a schematic structure of a glass chip;

3 shows a basic structure of a silicon chip with the electronics;

4 is a schematic representation of a speed control;

Fig. 5 is a schematic representation of a temperature control;

6 shows an embodiment of a meander-shaped structure for the capillary; and

Fig. 7 shows an embodiment of a structure in the form of a decision tree.

1 shows a device for transporting a microfluidic sample 110 in a capillary 130, which is formed in a substrate 120. The microfluidic sample 110 (which is often referred to as a sample hereinafter) moves between a first electrode 141 and a second electrode 142, passing a sensor 151 disposed along the capillary 130 between the first electrode 141 and the second electrode 142. The sensor 151 is adapted to perform a measurement with respect to the sample 110, for example, a top 110a and an end 110b of the sample 110 are detected and corresponding ^signals' to a controller 160 can be passed. For example, the controller 160 controls a voltage between the first electrode 141 and the second electrode 142 in response to a measurement result of the measurement, and thus determines the electric field E that affects the speed of the sample.

For example, the substrate 120 may include glass (or other transparent material) and may be formed on a substrate 125, wherein the substrate 125 may include a silicon chip or other semiconductor substrate and may include the controller 160.

FIG. 2 shows a plan view of the substrate 120 with the capillary 130, which has a meandering structure in the exemplary embodiment shown here. The capillary 130 connects an inflow reservoir 161 to a drain reservoir 162 and passes eight electrodes: a first electrode 141, a second electrode 142, a third electrode 143, a fourth electrode 144, a fifth electrode 145, a sixth electrode 146, a seventh Electrode 147 and an eighth electrode 148, wherein the second to seventh E- electrodes 142 to 147 are respectively arranged at vertices of the (rectangularly configured) meandering structure and the first electrode 141 as close as possible to the inflow reservoir 161 and the eighth electrode 148 close as possible the outflow reservoir 162 are arranged. The distance of the first electrode 141 to the inflow reservoir 161 and the distance of the eighth electrode 148 from the outflow reservoir 162 may be selected, for example, such that the most efficient possible uptake of liquid samples from the Inflow reservoir 161 and the most efficient possible delivery of the liquid samples 110 is given in the discharge reservoir 162. In the figure, the samples 110 are not shown.

The electronics 200 arranged in this plan view below the substrate 120 may, for example, be formed in a silicon chip. In this embodiment, the electronics 200 has a control sensor system 210, a sensor signal processor 220 (evaluation unit), an analog electronics 230, a user interface 240, an actuator 250, a control or a microcontroller 160 (control) and optionally a biochemical analysis 270 on. By means of the control sensor system 210, sensor signals are detected and passed on to the sensor signal processor 220, which in turn controls the actuator 250 by means of the analog electronics. In this case, the user interface 230 as well as the microcontroller 160 are used to influence the analogue electronics 230. This influence may depend, for example, on a biochemical analysis 270, if e.g. the sample speed becomes too fast to perform biochemical analyzes.

FIG. 3 shows a basic structure of the electronics 200 in the exemplary silicon and is complementary to the illustration in FIG. 2, that is to say the substrate 120 with the meandering capillary 130 which connects the inflow reservoir 161 to the drainage reservoir 162 scaled down shown on the left. 3 shows in more detail the electronics 200, wherein the control sensor system 210 may include, for example, a photosensor or a temperature sensor, and the sensor signal processing 220 should in particular enable low-noise signal processing. The analogue electronics 230 may comprise, for example, a formation of a reference voltage or of reference currents, a digitization, as well as a control of the actuators; the actuator 250 includes, for example, the electrodes 141 to 148 and a temperature controller. The micro- For example, the controller 160 may include / influence on flow control and control variables, and determines, for example, when the velocity of the sample 110 or a particular sample in a plurality of samples should be accelerated or decelerated, and passes corresponding signals to the analog electrode 230.

For example, user interface 240 includes a speed and temperature setting (e.g., target value) and may include a representation of actual sizes. Thus, the user can follow the analysis process and, if necessary, influence over the analog electronics 230. This influence can mean, for example, a speed change of a sample 110 as well as a temperature change of the sample 110. For example, the biochemical analysis 270 may include sensors (for biochemical data), signal processing, and signal presentation, and may optionally be coupled to the user interface 240 as well as to the microcontroller 160 to provide optimal conditions through an intervention of the user or the microcontroller 160 for biochemical analysis.

FIG. 4 shows an exemplary embodiment for a speed control of the electroosmotic flow 300. The electroosmotic flow 300 is performed via a measurement 310 by means of photosensors and the data are forwarded, for example, to a CMOS image processing electronics 320, which uses the measured data to generate a velocity. measurement 330. The measured speed is supplied to an actual-target comparison 350, which can, for example, record this data for different sample samples 110 and different channels and carry out a coordination. For this purpose, for example, corresponding setpoint values for the speed of the samples 110 can be supplied via a user interface 340. According to the result from the actual-target comparison 350, the speed is either increased (if the actual value is below the desired value). or the speed is reduced (if the actual value is above the target value). The influencing takes place via the controlled variables and a digital-analog converter 360, which in turn effects an electrode driver 370, whereby the electric field E (direction and amplitude) can be influenced. By a change in the electric field E in the electrode driver 370, there is finally a change 380 in the flow rate of all samples per channel or per capillary.

For example, the various channels may correspond to the straight sections of the meandering structure, i. The meandering structure of the capillary 130 may be formed by connecting various channels through the capillary 130 and, for example, containing a sample 110 in each channel. Furthermore, it is also possible that a plurality of capillaries can be arranged separately and can be controlled accordingly by a controller.

Fig. 5 shows a schematic representation of an embodiment of a temperature control. In this case, the samples 110 of the electroosmotic flow 300 are first detected by the photosensors 310 and their temperature determined by the temperature sensors 410. The photosensors 310 pass the corresponding signals (e.g., the times) to an image processing electronics 320, which may be based on, for example, CMOS technology, wherein in step 440 a measurement of the decrease in sample extension and a measurement of the sample velocity is made. If at least two electrodes are present, the speed can be achieved by detecting the starting point 110a of the sample 110 at different electrodes. Knowing the speed, a volume change or determination may be made by detecting the time interval between passing the start and end points 110a, 11Oe of the sample 110. This information can then be used to differentiate To influence samples with regard to their distance and their volume. The measurement of the sample expansion serves as a measure of evaporation and the measurement of the sample velocity (or its change) as a measure of a change in viscosity.

The signals of the temperature sensor 410 are forwarded to a signal processing electronics 420, which can also be based on a CMOS technology, and performs a temperature measurement step 430. The result of the temperature measurement 430 as well as the result of the sample expansion / sample rate measurement 440 are fed to an actual-target comparison 450. The actual-target comparison 450 coordinates, for example, all sample samples 110 and the channels, wherein the desired value can be input, for example via a U ser-interface 340. Alternatively, the target value may also be influenced, for example, by the biochemical analysis 270, thereby effecting an improvement in the biochemical analysis conditions. The result of the actual-target comparison 450 again serves to modify the electro-osmotic flow 300 or to change its temperature accordingly, with the aim of equalizing actual and target values. For this purpose, the result of the actual-nominal comparison 450 is converted via a digital-to-analog converter 460 in terms of the controlled variable and forwarded to a control for a thermocouple 470. The thermocouple 470, in turn, causes a change 480 in the temperature in the capillary or capillary sections and thus affects the electroosmotic flow 300 via the above-noted temperature dependence of both the viscosity and the zeta potential. As with the speed control, the temperature control, as has been explained in FIG. 5, can be carried out separately for different channels (channel 1 to channel n) or also for channel sections, in order thus to be able to influence individual samples 110. FIG. 6 shows an exemplary embodiment of the present invention for a meander-shaped structure of the capillary 130, which in turn connects the inflow reservoir 161 with the outflow reservoir 162.

At the top of FIG. 6, a top view is shown for the substrate 120, and at the bottom of FIG. 6, a cross-sectional view is shown through the substrate 120 and the ground substrate 125, which may include the electronics 200, for example.

FIG. 6A shows a top view of the meandering capillary 130 formed on or in the substrate 120. In this plan view, eight electrodes (141 to 148) are formed along a meander-shaped structure located in the (x, y) plane, and a first sample 501, a second sample 502, a third sample 503, and a fourth sample 504 are shown wherein the first sample intervenes between the first and second electrodes 141, 142; the second sample 502 between the third and fourth electrodes 143, 144; the third sample 503 is between the fifth and sixth electrodes 145, 146 and the fourth sample 504 is between the seventh and eighth electrodes 147, 148. The voltage between the eight electrodes can be selected, for example, such that the first to fourth sample are each at an equal distance from one another and pass through the meander-shaped capillary 130 at the same speed. Furthermore, eight photosensors are formed along the meandering capillary 130: first and second photosensors 151, 152 between the first and second electrodes 141, 142; third and fourth photosensors 153, 154 between the third and fourth electrodes 143, 144; a fifth and a sixth photosensor 155, 156 between the fifth and sixth electrodes 145, 146 and a seventh and eighth photosensor 157, 158 between the seventh and eighth electrodes 147, 148. Further, between the first and the second photosensor 151, 152, a first temperature sensor 521, between the third and the fourth photosensor 153, 154, a second temperature sensor 522, between the fifth and the sixth photosensor 155, 156, a third temperature sensor 523, arranged between the seventh and eighth photosensor 157, 158, a fourth temperature sensor 524. The eight photosensors 151 to 158 as well as the four temperature sensors 521 to 524 serve to detect the speed as well as the temperature of the samples 501 to 504 in turn in the previously described manner via a feedback to the applied voltage of the eight electrodes 141 to 148 can be influenced.

Furthermore, biochemical analyzes can be carried out by means of biosensors. In the embodiment shown in FIG. 6, a first biosensor 531 is interposed between the second electrode and the third electrode 142, 143; a second biosensor 532 between the fourth and fifth electrodes 144, 145; a third biosensor 533 is disposed between the sixth and seventh electrodes 146, 147. For example, the samples 501 to 504 pass first the biosensor 531, then the second biosensor 532, and finally the third biosensor 533, whereby the three biosensors 531 to 533 can make different measurements on the samples 501 to 504. By detecting the speed and temperature as described above, conditions can now be provided so that the biosensors 531 to 533 can find optimal sensor conditions.

Figure 6B shows a cross-section along the (z, x) plane through substrate 120 and sub-substrate 125, this cross-section taken along the XX 'line of Figure 6A. It thus shows the capillary 130 as it terminates in the drainage reservoir 162 and has the fourth sample 504. The fourth sample 504 is located between the seventh electrode 147 and the eighth electrode 148, and further along the capillary 130 is the fourth temperature sensor 524 located between the seventh and the eighth Photosensor 157 and 158 is shown. This cross-sectional view further shows the second biosensor 532 as well as the third biosensor 533, which are, however, arranged offset in the y-direction from the sectional plane.

Due to the plurality of electrodes 141 to 148, and the plurality of photosensors 151 to 158 as well as the plurality of thermal sensors / thermocouples 521 to 524, it is possible to separately control samples that are located simultaneously in the meandering capillary 130, as well as their speed and temperature separately to capture, to influence it. This allows a significantly higher sample throughput as well as optimal analysis conditions for the biosensors 531 to 533 - for each sample individually.

The embodiment shown in FIG. 6 thus shows in the upper section (FIG. 6A) a plan view of the exemplary glass chip 120, wherein apart from the electrodes 141 to 148 a possible distribution of photosensors 151 to 158 (two per channel) and the Temperature sensor / thermocouples 521 to 524 are indicated. In addition, the sensors for the actual biochemical analysis are shown (first to third biosensor 531 to 533). Thus, an example is shown in which the capillary 130 meanders over the exemplary glass chip 120 and has an inflow and outflow (inflow reservoir 161, outflow reservoir 162). Thus, a useful analysis (at the three biosensors 531 to 533) takes place in three places. Furthermore, four sample slots (501 to 504) are traveling in the channel system, all of which can be controlled individually via electrode pairs (that is to say via a voltage drop of adjacent electrodes). In the lower section (FIG. 6B), as stated, the sandwich structure of the structure of the exemplary glass chip 120 and a silicon chip 125 can be seen, wherein only the sensors are indicated, the electronics 200 and all interfaces are not shown. FIG. 7 shows a further embodiment in which the sample samples 110 pass a decision tree instead of the meandering structure of FIG. 6, the path being dependent on measurement results of the biosensors.

Figure 7A, similar to Figure 6A, shows a top view of the decision tree branching channel 130 connecting the inflow reservoir 161 to outflow reservoirs 162a-162h. The branches are arranged at different levels, each level having a plurality of electrodes. Thus, at a second level there are three electrodes 142a-c, at the third level four electrodes, etc. The numbering in the elements at the different levels is from top to bottom in Fig. 7. The electrodes serve to control the sample 110 and cause a change of direction. In the following, only a few branches will be explained.

A first branch of the decision tree takes place at the second electrode of the second level 142b, wherein a first electrode 141, the first biosensor 531 and the first photosensor 151 are arranged between the second electrode of the second level 142b and the inflow reservoir 161. The second electrode of the second level 142b is split into two channel regions, with one channel region leading to a first electrode of the second level 142a and the first channel region leading to a third electrode of the second level 142c. At the fourth electrode of the third level 143d and at the third electrode of the third level 143c, in turn, the first channel region and the second channel region are split, with a first between the second electrode of the third level 143b and the first electrode of the second level 142a Biosensor second level 532a and a first photosensor of the second level 152a are arranged. In the same way, between the third electrode of the third level 143c and the third electrode of the second level 142c, a second biosensor of the second level 532b and a second photosensor of the second level 152b are also arranged. The splitting of the channel at the second electrode of the third level 143b results in a third channel region and a fourth channel region, the third channel region having a first electrode of the third level 143a and between the first electrode of the third level 143a and the second electrode of the third level 143b a first photosensor of the third level 153a is arranged. The third channel region now leads from the first electrode of the third level 143a to the second electrode of the fourth level 144b, passing through a first biosensor of the third level 533a and a first photosensor of the fourth level 154a. At the second electrode of the fourth level 144b and at the fourth electrode of the fourth level 144d, in turn, a splitting takes place.

This splitting of the channel regions can continue in several steps, two electrodes in turn being arranged in a last channel region; in FIG. 7A this is, for example, the first electrode of the fourth level 144a and the last electrode 148a, between which a first biosensor of the fourth Levels 534a and a first photosensor of the fifth level 155a are arranged. Finally, the last channel region opens into the discharge reservoir 162a after passing the last electrode 148a. Different branching steps lead in the same way to the remaining outflow reservoirs 162b to 162h. Fig. 7A also shows a sample 110 located between the first electrode of the second level 142a and the second electrode of the third level 143b. The concrete path which the sample 110 will take can be chosen such that, for example, depending on the measurements on the biosensors 531 to 534, the path of the sample 110 is changed accordingly. For example, the various biosensors may perform various biochemical examinations such that upon a positive finding for a measurement result, the path is changed such that further analyzes are performed on the sample 110. In the same way as was also described in FIG. 6, several samples can pass through the channel 130 at the same time, the photosensors being able to detect the position of the individual samples as well as changes in the volume and via the controller 160 Speed of each sample and their spacing can be regulated with each other.

The top view in FIG. 7A is located in a (x, y) plane as in FIG. 6A, and FIG. 7B shows a cross section through this plane in the z direction along the XX ¹ section line from the inflow reservoir 161 to the outflow reservoir 162h (along the dash-and-dotted line in Fig. 7A).

In the cross-sectional view of Fig. 7B, in addition to the elements already described in Fig. 7A, further electrodes are drawn. The further electrodes can in particular support or improve transport by means of electrowetting. The further electrodes comprise, on the one hand, top electrodes 641 to 648 which, in the cross-sectional representation of FIG. 7B, are located above the channel 130. Find. Further, in the cross-sectional view of Fig. 7B, surface electrodes 741 to 748 are visible, which serve, for example, to change surface properties by potential differences between pairs of electrodes, thereby effecting control of the flux. Both the top electrodes 641 to 648 and the surface electrodes 741 to 748 are not shown in the plan view of FIG. 7A. All other elements shown in Fig. 7B are also shown in Fig. 6A. The substrate 120, as can be seen in FIG. 7B, includes a cap layer 120a, a channel region 120b, and a substrate substrate 125. The substrate substrate 125 may in turn comprise a silicon chip, for example, and the cover layer 120a as well as the channel region 120b may comprise a polymer (polymer chips) or glass.

Further exemplary embodiments provide a method for producing one of the abovementioned devices, which has, for example, the sandwich structure, transparent electrodes and electrical plated-through holes for contacting the electrodes (first electrode 141, top electrode 641, surface electrode 741, etc.). The electrodes 141, 641, 741 are permanently bonded or contacted in a soluble manner. This makes it possible to separate the substrate 120 (glass chip / polymer) and the silicon chip 125 from each other, so that the substrate 120 (with the channel 130) can be replaced after a single or multiple use or different substrates (eg with a meander-shaped structure or decision tree structure) can be placed on a substrate substrate 125 (on a silicon chip with the control / control) as needed. This is particularly possible when the electrodes are part of the substrate substrate 125 and makes the device flexible. Depending on the circumstances, the above embodiments may be implemented in hardware or in software. The implementation can be carried out on a digital storage medium, in particular a floppy disk, CD or DVD with electronically readable control signals, which can interact with a programmable computer system in such a way that the respective method is carried out. In general, the invention thus also consists in a software program product or a computer program product or a program product with a program code stored on a machine-readable carrier for carrying out the method according to the invention, if the software program product is stored on a computer program Computer or a processor expires. In other words, the invention can thus be realized as a computer program or software program or program with a program code for carrying out the method, when the program runs on a processor. The processor can in this case be formed by a computer, a smart card or another integrated circuit.

Claims

Claims:

1. A device for the simultaneous transport of a first and second microfluidic sample (501, 502) with:

a substrate (120);

a channel (130) formed in the substrate (120);

a plurality of electrodes disposed at different positions along the channel (130);

Sensors each disposed between electrode pairs of electrodes adjacent to each other along the channel and configured to perform measurements on the first and second microfluidic samples (501, 502);

a controller (160) for individually controlling voltage drops between the adjacent electrodes of the pairs of electrodes as a function of measurement results of the measurements.

2. Device according to claim 1, wherein the channel (130) is formed as a capillary or a structured substrate surface.

3. Device according to claim 1 or claim 2, wherein the plurality of sensors comprise a first photosensor (151) which is adapted to a point in time of a passing the microfluidic sample (110).

4. Apparatus according to claim 3, further

a second photosensor (152) and the second photosensor (152) is adapted to detect a further time of passing the microfluidic sample (110) on the second photosensor (152); and

an evaluation unit (220) which is designed to determine a speed of the microfluidic sample (110) from a difference between the time and the further point in time.

A device according to claim 4, wherein the first and second photosensors (151, 152) are part of a photo line.

A device according to claim 4 or claim 5, wherein one of the microfluidic samples (110) has a beginning (110a) and an end (11Oe), the beginning (110a) being transported before the end (11Oe), the first photosensor (110). 151) and then passing the second photosensor (152),

wherein the first and second photosensors (151, 152) are configured to detect the time of passing by the time of passing the start (110a) of the microfluidic sample (110).

7. The device according to claim 6, wherein the first photosensor (151) or second photosensor (152) is configured to detect a time interval between the passage of the start (110a) and the end (11Oe) of the microfluidic sample (110) , and further wherein the evaluation unit (220) is adapted to determine a volume of the microfluidic sample (110) from the time difference.

8. Apparatus according to claim 7, comprising further photosensors (153) to (158),

wherein at least one of the further photosensors (153) to (158) is likewise designed to detect the time interval and the evaluation unit (220) is adapted to detect a change in the volume of the microfluidic sample (110) and, above this, a change in a temperature of the microfluid - to determine sample (110).

9. Apparatus according to claim 8, wherein the evaluation unit (220) is designed to change the voltage between the electrode pairs such that the speed and / or the temperature is below a threshold value.

10. The device of claim 1, further comprising a temperature sensor and the temperature sensor configured to determine a temperature of one of the microfluidic samples.

11. The device according to claim 10, wherein the temperature sensor is designed, a temperature output value and in which the evaluation unit (220) is designed to determine from the change in the volume of the microfluidic sample (110) a temperature deviation from the temperature output value.

The apparatus of any one of the preceding claims, further comprising a thermocouple for changing the temperature of one of the microfluidic samples (110).

13. The device of claim 1, wherein the plurality of electrodes are configured to change a velocity of one of the microfluidic samples along the channel.

14. The apparatus according to claim 13, wherein the control

(160) is adapted to adjust voltage drops between the electrode pairs such that a distance between the first microfluidic sample (501) and the second microfluidic sample (502) is above a threshold value.

15. Device according to one of the preceding claims, further comprising a biosensor (531) which is designed to detect ingredients and / or biochemical properties of the microfluidic sample (110).

16. Device according to one of the preceding claims, further comprising a further channel portion, wherein along the further channel portion further sensors are each arranged between further pairs of electrodes and formed the further sensors are to carry out further measurements with respect to further microfluidic samples.

17. The apparatus of claim 15, wherein the channel (130) comprises a decision tree and the controller

(160) is adapted to determine a path of the microfluidic sample (110) along the decision tree in dependence on detected data of the biosensor (531).

18. Device according to one of the preceding claims, wherein the channel (130) has a meandering structure.

19. The device according to claim 1, wherein the plurality of electrodes has a first electrode and the device further comprises a top electrode and the top electrode on a side opposite to the first electrode the channel (130) is arranged.

20. Device according to one of the preceding claims, wherein the controller (160) is formed in a substrate substrate (125), the substrate (120) has a channel region (120b) and a cover layer (120a), such that the channel region (120b) between the under substrate (125) and the cover layer (120b).

The apparatus of claim 20, wherein the substrate substrate (125) is detachably connected to substrate (120).

22. The device according to claim 19 or claim 20, wherein a surface electrode (741), the top electrode (641) or the first electrode (141) comprise a transparent material.

23. Device according to one of the preceding claims, wherein the substrate (120) comprises a transparent material.

24. The device of claim 23, wherein the substrate (120) comprises a polymer or glass and / or the sub- strate substrate (125) comprises silicon.

25. Device according to one of the preceding claims, in which an inner wall of the channel (130) has a coating and the coating is designed, the speed of the microfluidic sample

(110) influence.

26. The device according to claim 25, wherein the coating comprises neutral hydrophilic polymers and / or has a covalent coating.

27. Device according to one of the preceding claims, wherein the controller (160) is further adapted to introduce into the channel (130) a further means, wherein the further means is designed, the speed and / or the temperature of the microfluidic sample (110 ) to change.

28. A method for simultaneously transporting a first and second microfluidic sample (501, 502) comprising: Providing a substrate having a channel and a plurality of electrodes disposed at different positions along the channel (130);

Measuring quantities relative to the first and second microfluidic samples (501, 502) during transport between electrode pairs of adjacent electrodes; and

Individual regulation of voltage drops between the adjacent electrodes of the electrode pairs depending on the measured quantities.

29. A method for producing a device for the simultaneous transport of a first and second microfluidic sample (501, 502), comprising the following steps:

Providing a substrate (120);

Forming a channel (130) in the substrate (120);

Forming a plurality of electrodes at different positions along the channel (130);

Forming sensors between pairs of electrodes of adjacent electrodes, the sensors being configured to perform measurements on the first and second microfluidic samples (501, 502); and

Forming a controller (160) for individually regulating voltage drops between the adjacent electric electrodes of the electrode pairs as a function of measurement results of the measurements.

A program code program for carrying out the method of claim 28 or claim 29 when the program is run on a processor.