MXPA99000036A - Variable control of the electroosmotic and / or electroforetic forces inside a quecony structure flush via electricity forces - Google Patents

Abstract

The present invention relates to a microfluidic system (partially shown by element 178 in the figure and elements therein), which uses electrokinetic forces, the present invention uses electric current or electrical parameters, other than voltage, to control the movement of fluids through the system channels. The time multiplexed energy supplies (200 and 202) also provide additional control over the movement of the fluid by varying the voltage on an electrode connected to a fluid reservoir of the microfluidic system, causing a variable duty cycle to vary during which the voltage is applied to the electrode, or by means of a combination of both. It can also be connected a power supply multiplexed by time to more than one electrode to save on cost

Description

VARIABLE CONTROL OF XAS FORCES ELECTROOSMOTICAg AND / OR ELECTROPHORETICS WITHIN TJNA STRUCTURE. WHICH CONTAINS FLUID VIA ELECTRIC FORCES BACKGROUND OF THE INVENTION There has been an increasing interest in the manufacture and use of microfluidic systems for obtaining chemical and biochemical information. The techniques commonly associated with the electronic industry of semiconductors, such as photolithography, wet chemical etching, etc., are being used in the manufacture of these microfluidic systems. The term, 'microfluidic' refers to a system or device that has channels and chambers, which are generally manufactured to scale micronic or sub-ionic, for example, that have at least one cross-sectional dimension • in the range of "approximately 0.1 μm to approximately 500 μm The first discussions of the use of the technology of flat integrated microcircuits for the manufacture of microfluidic systems are provided in Manz et al., Trends in Anal. Chem. (1990) .10 (5): 144-149 and Manz et al., Avd. In Chromatog. (1993) 33: 1-66, which describe the manufacture of such fluidic devices and particularly microcapillary devices, on silica and glass substrates.

The applications of microfluidic systems are counted in thousands. For example, International Patent Application WO 96/04547, published on February 15, 1996, describes the use of microfluidic systems for capillary electrophoresis, liquid chromatography, flow injection analysis and chemical synthesis and reactions. US Patent Application No. Application,, entitled * HIGH PERFORMANCE SELECTION TEST SYSTEMS1 IN FLUIDIC DEVICES TO MICROESCAL ,,, presented on June 28, 1996, by J. Wallace Parce et al. and assigned to the present beneficiary, describes a wide range of applications of microfluidic systems to rapidly test a large number of compounds for their effects on various chemicals, and preferably, biochemical systems. The phrase, "biochemical system", refers generally to a chemical interaction, which involves molecules of the type generally found within living organisms, such interactions include the full range of catabolic and anabolic reactions that occur in living systems, including enzymatic reactions, binding, signaling and others Biochemical systems of particular interest include, for example, receptor-ligand interactions, enzyme-substrate interactions, cellular signaling pathways, transport reactions involving model barrier systems (eg, example, cellular or membrane fractions) for selection by bioavailability, and a variety of other general systems Many methods for the transport and direction of fluids, eg, samples, analytes, buffers and reagents, have been described within those systems. or microfluidic devices: a method moves fluids within a device Metered by micro-pumps and valves inside the device. See, British Patent Application No. 2 248 891 (10/18/90), Patent Application -g ^ European No. 568 902 (5/2/92) Published, Patents Americans Nos. 5,271,724 (8/21/91) and 5,277,556 (3/7/91). See also, U.S. Patent No. 5,171,132 (12/21/90) of Miyaza et al. Another method uses acoustic energy to move fluid samples within devices by the effects of acoustic cavitation.

See, PCT Application No. 94/05414 of Northrup and White, Published. A simple method applies external pressure to move fluids inside the device. See, for example, the discussion in U.S. Patent No. 5,304,487 to ilding et al. Another yet another method uses electric fields, and the result of electrokinetic forces, to move fluid materials through the channels of the microfluidic system. See, for example, European Patent Application No. 376 611 (12/30/88) by Kovacs, Harrison et al., Anal. Chem. (1992) 64 1926-1932 and Manz et al. J. Chromatog. (1992) 593: 253-258, U.S. Patent No. 5,126,022 to Soane. Electrokinetic forces have the advantages of direct control, rapid response and simplicity. However, there are still some disadvantages with this method of operation for microfluidic systems. Current devices use a network of channels in a substrate of electrically insulating material. The channels connect a number of fluid reservoirs in contact with high voltage electrodes. To move fluid materials through the network of channels, specific voltages are applied simultaneously to the different electrodes. The determination of the values of the voltage for each electrode in n system, becomes complex when trying to control the flow of material in one channel without affecting the flow in another channel. For example, in a relatively simple arrangement of four channels that intersect at a junction with reservoirs and electrodes at the ends of the channels, an independent increase in fluid flow between two reservoirs is not simply a matter of increasing the voltage differences at the ends of the channels. two reservoirs. The voltages in the other two reservoirs must also be adjusted and their original flow and direction must be maintained. In addition, when the number of channels, intersections and reservoirs increases, control of the fluid through the channels becomes more and more complex.

Also, the voltages applied to the electrodes in the device can be high, that is, up to a level that supports thousands of volts / cm. Highly regulated voltage supplies are expensive, bulky and often inaccurate and a high voltage supply is required for each electrode. In this way, the cost of a microfluidic system of any complexity can become prohibitive. The present invention solves or substantially alleviates these problems of electrokinetic transport, in a microfluidic system that uses another electrical parameter, instead of voltage, to simplify the control of the flow of material through the channels of the system. A high performance microfluidic system that has a direct, fast and simple control over the movement of materials through the channels of the microfluidic system with a wide range of applications, such as in the fields of chemistry, biochemistry, biotechnology and molecular biology and other numerous fields, it is possible.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a microfluidic system, with a plurality of interconnected capillary channels and a plurality of electrodes in the different nodes of the capillary channels, which creates electric fields in the capillary channels to electrolytically move materials in a fluid through the capillary channels. According to the present invention, the microfluidic system is operated by applying a voltage between a first electrode and a second electrode that responds to an electric current between the first and second electrodes, to move the materials between them. The electric current can give a direct measurement of the ionic flux through the channels of the microfluidic system. In addition to the current, other electrical parameters, such as electrical power, can also be used. Furthermore, the present invention provides the time multiplexing of the voltages of the electric power supply on the microfluidic system electrodes for more precise and efficient control. The voltage for an electrode can be controlled by varying the duty cycle of the electrode connection to the power supply, by varying the voltage to the electrode during the duty cycle, or a combination of both. In this way, an energy supply can serve more than one electrode. The present invention also provides direct verification of the voltages within the channels in the microfluidic system. The conductive wires on the surface of the microfluidic system have sufficiently narrow widths, in a channel to prevent electrolysis. The wires are also connected in the voltage divider circuits on the surface of the substrate. The divider circuit decreases the read voltage of the channel node, so that special high voltage voltmeters are not required. The divider circuits are also designed to discharge negligible streams of the channels by minimizing, therefore, the undesirable electrochemical effects, eg, gas generation, reduction / oxidation reactions. The invention so far described can be placed in a plurality of different uses, which are themselves inventive, for example, as follows: The use of a substrate having at least one channel, in which an object material is electrokinetically transported , by applying a voltage between two electrodes associated with the channel in response to a current in the electrodes. Using the aforementioned invention, in which the substrate has a plurality of interconnected channels and associated electrodes, the target material is transported along predetermined paths incorporating one or more of the channels by applying voltages to predetermined electrodes in response to a current in the electrodes.

The use of a substrate having at least one channel in which an object material is electrokinetically transported by the time-dependent, controlled application of an electrical parameter between electrodes associated with the channel. The use of the aforementioned invention, wherein the electrical parameter comprises voltage, current or electric power. The use of an insulating substrate having a plurality of channels and a plurality of electrodes associated with the channels, the application of voltages to the electrodes causes the electric fields in the channels, and at least one conducting wire on the substrate to extend towards the location of a channel, so that an electrical parameter can be determined in the location of the channel. The use of the aforementioned invention, wherein the conductor wire has a sufficiently small width, so that the voltage is less than 1 volt, and preferably less than 0.1 volt, is created through the conductive wire in the location of the channel. The use of an insulating substrate having a plurality of interconnected capillary channels, a plurality of electrodes in different nodes of the capillary channels to create electric fields in the capillary channels to move materials electrokinetically in a fluid through the capillary channels, a supply of energy connected to at least one of the electrodes, the power supply has a mixing block having a first input terminal for receiving a controllable reference assembly and a second input terminal, and an output terminal; a voltage amplifier connected to the output terminal of the mixing block, the voltage amplifier has first and second output terminals, the first output terminal connected to at least one electrode; and a feedback block connected to the first output terminal of the voltage amplifier, the feedback block has an output terminal connected to the second input terminal of the mixing block, so that negative feedback is provided to stabilize the supply of Energy. The use of the aforementioned invention, in which the feedback block is also connected to the second output terminal of the voltage amplifier, the feedback block that generates a first feedback voltage responds to a voltage at the first output terminal and a second feedback voltage responds to a quantity of current that is being delivered to at least one electrode through the first output terminal / feedback block having a switch to pass the first or second feedback voltage to the control block. mixed responds to a control signal, so that the power supply is selectively stabilized by voltage or current feedback. The use of a power supply to connect to at least one electrode of a microfluidic system, in which the power supply has a mixing block having a first input terminal for receiving a controllable reference voltage and a second control terminal. entrance and an exit terminal; a voltage amplifier connected to the output terminal of the mixing block, the voltage amplifier has first and second output terminals, the first output terminal connected to at least one electrode; and a feedback block connected to the first and second output terminals of the voltage amplifier and to the second input terminal of the mixing block, the feedback block that generates a first feedback voltage responds to a voltage at the first output terminal and a second feedback voltage responds to a quantity of the current delivered to at least one electrode through the first output terminal, the feedback block having a switch to pass the first or second feedback voltage to the mixing block responds to a control signal, so that the power supply is selectively stabilized in voltage or current by negative feedback. The use of a microfluidic system in which a substrate has a plurality of interconnected capillary channels, a plurality of electrodes in different nodes of the capillary channels to create electric fields in the capillary channels to move materials electrokinetically in a fluid through the channels capillaries and a plurality of power supplies connected to each of the electrodes, each of the power supplies is capable of selectively supplying a selected voltage and a selected amount of current as a source or 'sink' of the connected electrodes.

BRIEF FRESCR PIONE OF THE DRAWINGS Figure 1 shows a representative illustration of a microfluidic system; Figure 2A illustrates an exemplary channel of a microfluidic system, such as that of Figure 1; Figure 2B represents the electrical circuit created along the channel in Figure 2A; Figure 3A is a graph of the output voltage versus the time for a power supply of the prior art; Figure 3B is a graph of the output voltage versus time for a multiplexed time power supply according to the present invention; Figure 4A is a representative illustration of a microfluidic system operating with the time multiplexed voltages according to the present invention; Figure 4B is a block diagram illustrating the units of a power supply in Figure 4A; Figure 5A is a representative illustration of a microfluidic system with voltage verified nodes according to the present invention; Figure 5B details the voltage divider circuit of Figure 5A, and Figure 6A is a block diagram of the power supply unit of Figure 4B; Figure 6B is a representation of the amplifier block of the CD-CD converter block of, Figure 6A.

DETAILED DESCRIPTION OF THE INVENTION Figure 1 depicts a representative diagram of a portion of an exemplary microfluidic system 100 operating in accordance with the present invention. As shown, the total device 100 was fabricated on a flat substrate 102. Suitable substrate materials are generally selected based on their compatibility with the conditions present in the particular operation to be effected by the device. Such conditions may include the extremes of pH, temperature, ionic concentration and application of electric fields. Additionally, the substrate materials are also selected to be inert to the critical components of an analysis or synthesis to be carried out by the system. The system shown in Figure 1 includes a series of channels 110, 112, 114 and 116 fabricated on the surface of the substrate 102. As discussed in the definition of 'microfluidic', these channels typically have very small cross-sectional dimensions.For the particular applications discussed below, the channels with depths of approximately 10μm and widths of approximately 60 μm work effectively, although deviations from these dimensions are also possible The microfluidic system 100 transports target materials through the different channels of the substrate 102 for various purposes, including analysis, testing, mixing with other materials, testing and combinations of those The term, 'object materials', simply refers to the ial, such as a chemical or biological compound, of interest. The subject compounds may include a wide variety of different compounds, including chemical compounds, mixtures of chemical compounds, for example, polysaccharides, small organic or inorganic molecules, biological macromolecules, eg, peptides, proteins, nucleic acids or extracts made from biological materials. , such as bacteria, plants, fungi or animal cells or tissues, natural or synthetic compositions. Useful substrate materials include, for example, glass, quartz, ceramics and silicon, as well as polymeric substrates, e.g., plastics. In the case of conductive or semiconducting substrates, there must be an insulating layer on the substrate. This is important, since the system uses electroosmotic forces to move materials around the system, as discussed below. In the case of polymeric substrates, the substrate materials may be rigid, semi-rigid or non-rigid, opaque, semi-opaque or transparent, depending on the use for which they are intended. For example, systems that include an optical or visual detection element, are generally manufactured, at least in part, from transparent materials to allow, or at least, facilitate that detection. Alternatively, transparent glass or quartz windows may be incorporated, for example, in the device for those types of detection elements. Additionally, the polymeric materials may have linear or branched backbones, and may be crosslinked or non-crosslinked. Examples of particularly preferred polymeric materials include, for example, polydimethylsiloxanes (PDMS), polyurethane, polyvinyl chloride (PVC), polystyrene, polysulfone, polycarbonate, polymethacrylate (PMMA), and the like. The manufacture of these channels and other microscale elements on the surface of the substrate 102 can be carried out by any number of microfabrication techniques that are well known in the art. For example, lithographic techniques can be employed to manufacture glass, quartz or silicon substrates, for example, with methods well known in the semiconductor manufacturing industries. Photolithographic masking, chemical plasma or wet etching, and other semiconductor processing technologies define microscale elements on and or substrate surfaces. Alternatively, micromachining methods, such as laser drilling, microabrasion and the like, can also be employed. Similarly, for polymeric substrates, well-known manufacturing techniques can also be used. These techniques include injection molding techniques or stamping molding methods where a large number of substrates can be produced using, for example, lamellar stamps to produce large sheets and microscale substrates or polymer micromolding techniques, where The substrate is polymerized within a micro-machined mold. In addition to the substrate 102, the microfluidic system 100 includes an additional flat element (not shown) which coats the fluted substrate 102 to fluidly seal and seal the different channels to form ducts. The flat cover element can be attached to the substrate by a variety of means, including / for example, thermal bonding, adhesives or, in the case of certain substrates, for example, glass, or semi-rigid and non-rigid polymer substrates ^ an adhesion natural between the two components. The flat cover element can additionally be provided with access doors and / or reservoirs to introduce the different fluid elements necessary for a particular screen. The system 100 shown in Figure 1 also includes the reservoirs 104, 106 and 108, which are located and connected fluidly at the ends of the channels 114, 116 and 110 respectively. As shown, channel 112 is used to introduce a plurality of different target materials into the device. As such, channel 112 is fluidly connected to a source of a large number of separate object materials, which are individually introduced into channel 112 and subsequently into another channel 110 for electrochromic analysis, for example. The target materials are transported in cylindrical regions of fluid 120 of predetermined ionic concentrations. The regions are separated by buffer regions of various ionic concentrations and represented by the buffer regions 121 in Figure 1. Related patent applications, US Patent Application No. 08 / 671,986, filed on June 28, 1996, and Application US Patent No. 08 / 760,446, filed on December 6, 1996, both entitled 'ELECTROPIPETTE MEDIA AND COMPENSATION FOR ELECTROPHORETIC DEVIATION' by J. Wallace Parce and Michael R. Knapp, and granted to the beneficiary of this, explain various arrangements of cylindrical and buffer regions of high and low ionic concentrations in the transport of target materials with electrokinetic forces Applications are hereby incorporated as a reference in their entirety for all purposes To move materials through channels 110, 112, 114 and 116, a voltage controller can be used, which is capable of applying simultaneously selectable voltage levels, including a ground connection, to each of the reservoirs. Such a voltage controller can be implemented using multiple voltage splitters and relays to obtain the selectable voltage levels. Alternatively, multiple independent voltage sources can be used. The voltage controller is electrically connected to each of the reservoirs via an electrode placed or manufactured within each of the reservoirs 104, 106 and 108. See, for example, published International Patent Application No. WO 96/04547 of Ramsey, which is here incorporated as a reference in its entirety for all purposes. In addition to complexity, there are other problems with voltage control in a microfluidic system. Figure 2A illustrates an exemplary channel 130 between two reservoirs 132 and 134, each respectively in contact with electrodes 133 and 135, connected to wires or electrical wires shown exiting the substrate 128. To make the example more realistic, channel 130 is it shows as if it were connected to two other channels 136 and 138. Operationally, the reservoir 132 is a source for cylindrical portions 120 containing the subject material. The cylindrical portions 120 move towards the reservoir 134, which acts as a collector or dissipater. The channels 136 and 138 provide buffer regions 121 for separating the cylindrical portions 120 in the channel 130. The different resistances of the cylindrical portions 120 and the buffer regions 121 in the channel 130 create an electrical circuit, which is symbolically indicated in this example. The voltage V applied between the two electrodes 133 and 135 is: SAW ?? • = 0! where I is the current between the two electrodes 133, 135! (assuming there is no current flow to 136, 138) and Ri is the resistance of the different cylindrical portions 120 and the buffer regions 121. A voltage control system is subject to many factors, which can interfere with the operation of the system. For example, the contact in the I interface between an electrode and the fluid can be a source of problems. When the effective resistance of the contact of the electrode to the fluid varies due to contaminants, bubbles, oxidation, for example, the voltage applied to the fluid varies. I With fixed V on the electrodes, a decrease in the surface area of the electrode in contact with the solution due to the formation of bubbles on the electrode, causes an increase in the resistance of the electrode to the solution. This reduces the current between the electrodes, which in turn reduces the electroosmotic and electrophoretic forces induced in the channel 130. Other problems can affect the current flow of the channel. Undesirable particles can affect the strength of the channel by effectively modifying the cross-sectional area of the channel. Again, with a change in channel resistance, the physical current flow changes. With other channels, such as channels 136 and 138, connected to exemplary channel 130, dimensional variations in the geometry of the channels in substrate 102 can seriously affect the operation of a voltage control system. For example, the intersection node for channels 130, 136 and 138 may be X distance of the electrode for the reservoir in terms of channel 136 (not shown) and Y distance of the electrode for the reservoir at the terminal end of channel 138 ( it is not shown). With a slight misalignment. Lateral in the photolithographic process, the distances X and Y are no longer the same for the microfluidic system on another substrate. Voltage control must be recalibrated from substrate to substrate, a process that is expensive and time-consuming, so that fluid movement at the intersection node can be controlled appropriately. In order to avoid such problems, the present invention utilizes the control of the electric current in the microfluidic system 100. The flow of electric current in a given electrode is directly related to the ionic flux along the channels connecting the reservoir in which the electrode is placed. This contrasts with the requirement to determine the voltages at different nodes along the channel in a voltage control system. In this way, the voltages in the electrodes of the microfluidic system 100 respond to the electric current flowing through the different electrodes of the system 100. The current control is less susceptible to dimensional variations in the process of creating the microfluidic system on the substrate 102. Current control makes it easier to pump, valve, distribute, mix and concentrate the target materials and buffer fluids in a complex microfluidic system. Current control is also preferred to moderate the undesirable temperature effects within the channels. Of course, in addition to the electric current, which provides a direct measurement of the ion flow between the electrodes, other electrical parameters related to the current, such as electrical power, can be used as a control for the microfluidic system 100. Electric power gives an indirect measurement of the electric current through an electrode. Consequently, the physical current between the electrodes (and the ionic flux) can be verified by the electric current through the electrodes. Even with a current control system described above, high voltages must still be applied to the electrodes of the microfluidic system. To eliminate the need for expensive energy supplies, which are capable of generating continuous and accurate voltages, the present invention provides power supplies, which are multiplexed by time. Those time-multiplexed power supplies also reduce the number of power supplies required for the system 100, since more than one electrode can be served by a multiplexed time power supply. Figure 3A illustrates the exemplary output of a high energy supply currently used in an electrokinetic system. The output is constant at 250 volts between two electrodes over time. In contrast, Figure 3B illustrates the output of an energy supply operating in accordance with the present invention. To maintain a constant voltage of 250 volts, the output voltage is multiplexed by time with a duty cycle of one quarter to 1000 volts. Averaged over time, the voltage supply output multiplies by time is 250 volts, as illustrated by the dotted horizontal line through the graph. Note that if the voltage should change, say, in response to current control, as discussed above, the output voltage of the multiplexed time power supply may also change due to a change in the applied voltage, or by a change in the work cycle, or a combination of both. The flow of electroosmotic fluid can start and stop on a time scale of μseconds in the channels of the dimensions described above. Therefore, voltage modulation frequencies that are less than one Megahertz result in an uncertain movement of the fluids. This will have no adverse effects on fluid handling due to the nature of the piston flow of the electroosmotic fluid. Because most chemical mixing, incubation, and separation events occur at a time scale of 0.1 to 100 seconds, most of the lower frequencies for voltage manipulation may be acceptable. As an empirical rule, the modulation period should be less than 1% of the shortest switching event (eg, a switching flow from one channel to another) to keep mixing or pipetting errors below 1%. For a switching event of 0.1 seconds, a voltage modulation frequency should be 1 KHz or higher. Figure 4A is a block diagram of a multiplexed power supply system with two power supplies 200 and 202 and the controller block 204 for an exemplary and simple microfluidic system having a channel 180, which intersects channels 182, 184, 186 and 188. Channel 180 terminates in reservoirs 179 and 181 with electrodes 190 and 191 respectively, channel 182 ends with a reservoir 183 having an electrode 193.; channel 184 ends with a reservoir 185 having an electrode 195; channel 186 with reservoir 187 having an electrode 197; and channel 188 with reservoir 189 having an electrode 199. Power supplies 200 and 202 are connected to different electrodes 190, 191, 193, 195, 197 and 199 of the microfluidic system. The power supply 200 is connected to three electrodes 190, 193 and 195, and the power supply 202 is connected to the three remaining electrodes 191, 197 and 199. The controller block 204 is connected to each of the power supplies 200 and 202 to coordinate their operations. For example, to control the movements of the fluids through channels 182, 184, 186 and 188, the voltages on the electrodes 190, 191, 193, 195, 197 and 199 must be properly synchronized. The voltages in the electrodes change in response to the flow of electrical current, as described above, for example, when the controller block 204 directs the power supplies 200 and 202. Each of the power supplies 200 and 202 are organized in the units illustrated in Figure 4B. A control unit 212 receives control signals from the control block 204 and directs the operation of a switching unit 214. The switching unit 214, connected to a power supply unit 216, makes or interrupts the connections of the control unit. power supply 216 to the connected electrodes. In other words, the Switching unit 214 multiplexes by time the energy of the power supply unit 216 between its connected electrodes. The power supply unit 216 is also connected to the control unit 212 which directs the variation of the output of the power supply unit 216 to the switching unit 214. In an alternative arrangement, this connection to the power unit control 212 is not required if the power supply unit 216 supplies a constant voltage and the average voltage to an electrode changes by varying the duty cycle of the connection through the switching unit 214. FIG. 6A is a flow chart blocks of a power supply, which could be used as the power supply unit 216 in Figure 4B. Alternatively, the illustrated power supply can be connected directly to an electrode of a microfluidic system if time multiplexing is not used. The power supply can supply a stable voltage to an electrode or supply, or dissipate, a stable current. The power supply has an input terminal 240, which is supplied with a controllable reference voltage of -5 to +5 volts, which is graduated in magnitude up to hundreds of volts at an output terminal 241. The input terminal is connected to the negative input terminal of an input operational amplifier 230 through a resistor 227. The positive input terminal of an operational amplifier 230 is connected to ground and its output terminal is again connected to the negative input terminal through a feedback capacitor 220 and resistor 228 connected in series. The output terminal is also connected to an input terminal of a CD-to-CD converter 231. A second input terminal is connected to ground. The output side of the converter 231, which gradually raises the voltage received from the amplifier 230, is connected to the output terminal of the power supply 241. The second output terminal of the converter 231 is connected to ground through a resistor 222 The output terminal of the power supply 241 is also connected to ground through two resistors connected in series 221 and 223, which form a voltage divider circuit. The node between the two resistors 221 and 223 is connected to an input terminal of a current / voltage mode switch 234The node is also connected to the negative input terminal of an operational feedback amplifier 232 through a resistor 225. The negative input termination is also connected to the output terminal of the converter 231 through a resistor 224 and the output terminal of the amplifier 232 through a feedback resistor 226. The output terminal of the amplifier 232 is also connected to a second input terminal of the switch 234, which has its output terminal connected to the negative input terminal of the input operational amplifier 230 through a resistor 226. The switch 234 responds to a signal on the control terminal 242. As shown in Figure 6A, the switch 234 connects its output terminal to any output terminal of the amplifier. operational feedback 232, or to the voltage dividing node between the two resistors 221 and 223. The connection determines if the power supply circuit operates in the voltage mode (connection to the voltage divider node) or in the current mode (connection to the output of the operational feedback amplifier 232). Note that the resistor 221 is very large, approximately 15 Q, of odp that the voltage on the output terminal 241 can be easily fed back when the power supply is operated. The circuit of Figure 6A can be separated into different operational blocks. The operational amplifier 230, the resistors 225-228 and the capacitor 220 are part of a mixing block. The mixing block accepts the controllable reference voltage Vref, at which the power supply operates, at the input terminal 240 and a feedback voltage, as discussed below, to generate an output voltage, a combination of Vref and feedback voltages, for the CD-CD converter 231. The converter 231, illustrated as a voltage amplifier in FIG. 6B, simply amplifies the voltage of the operational amplifier 230. An output terminal of the voltage amplifier is connected to the amplifier. the output terminal 241 and a terminal of the resistor 221. The other output of the voltage amplifier is connected to ground through the resistor 222. The resistors 221-223 can be considered as part of a feedback block, which also has resistors 224-226 and an operational amplifier 232. Switch 234 is also part of the feedback block and is connected to the second input terminal of the mixing block, as described above. Operationally, the mixing block has the operational amplifier 230, which is connected as a summing amplifier with the resistors 226-228. With the capacitor 220 in the feedback loop of the operational amplifier 230, the output voltage of the operational amplifier 230 is the integrated voltage over time of the sum (or difference) of the reference voltage Vref and the feedback voltage of the switch 234. Of course, the reference voltage Vref and the feedback voltage can be selectively weighted by the values of the resistors 226 and 227. The capacitor 220 and the amplifier 230 also act as filters to remove high frequency fluctuations from the power supply. The output signal of the operational amplifier 230 can be conditioned, for example, rectified or damped, by additional elements (not shown). However, for the purposes of understanding this invention, VSN, the voltage received by the CD-CD converter 231 can be considered the same as the output voltage of the operational amplifier 230. As shown in Figure 6B, V N is amplified by a gain factor A and the amplified voltage AVIN is generated on the output terminal 241. The feedback block has a voltage divider circuit formed by the resistors 221 and 223 connected between the output terminal 241 and the ground connection. The voltage at the node between the resistors 221 and 223 is directly proportional to the voltage at the output terminal 241. When the switch 234 in response to the signal on the control terminal 242 selects the voltage feedback mode, the voltage of the node is fed directly back to the mixing block and the operational amplifier 230. The negative feedback stabilizes the output in the terminal 241. Ppr example, if the voltage in the terminal 241 is high, the feedback voltage is high . This, in turn, causes the output voltage of the operational amplifier 230 to drop, thereby correcting the high voltage at the output terminal 241. To verify the voltage at the output terminal 241, the node is also connected to a operational amplifier 251, configured as a simple buffer, to send the feedback voltage to a tester circuit (not shown). The feedback block also has the operational amplifier 232 and the resistors 224-226, which are connected to configure the operational amplifier 232 as an adder amplifier. An input to the summing amplifier is connected to the node between the resistors 221 and 223. The second input is connected to the node between the resistor 222 connected to ground and the second output terminal of the CD-CD converter 231. The summing amplifier measures the difference between the amount of current through the resistors connected to series 221 and 223 and through converter 231 (the total current through resistors 222 and 224). In effect, the summing amplifier measures the amount of current that is being delivered through the output terminal 241. In this way when the switch 234 is set in the current feedback mode, the output of the operational amplifier 232 acts as a summing amplifier is sent to the mixing block and the power supply circuit is stabilized at approximately the amount of current that is being delivered or released through the terminal of the power supply 241 to an electrode connected in a microfluidic system. The output of the summed amplifier is also connected to an operational amplifier 250, configured as a simple buffer, to send the output voltage to the verifier circuit (not shown). From the outputs of the operational amplifiers 250 and 251, the tester circuit has a measurement of the voltage at the output terminal 241 and the current through the terminal. This also allows the verification of the circuit to determine, and to regulate, the amount of energy that is being supplied to the power supply circuit. The ability of the described power supply to act as a variable source allows the flow direction of the fluid through the microchannels of the microfluidic system to be changed electronically. If all the electrodes are connected to one or more of the energy supplies described above, the operation of the microfluidic system is greatly improved and the desired movements of the fluids through the network of channels in the system are much more flexible. Despite the operation as a current control system, there is often a need to determine the voltage at a node in a microfluidic system. The present invention also provides means for verifying such a voltage. As shown in Figure 5A, an electrical wire 160 is formed on the surface of a substrate 178 near a desired node 173 in the microfluidic system. The node 173 is at the intersection of channel 170 having reservoirs 169 and 171 at each end and channels 172 and 174. The terminus of channel 174 has a reservoir 175, while the terminus of channel 172 (and a reservoir) it is not shown. The wire or cable 160 is preferably formed by the deposition of a conductive metal, or metal alloy, preferably a noble metal, such as gold on chromium or platinum on titanium, used in integrated circuit. With the techniques of semiconductor photolithography, the wire 160 can be defined with widths of less than 1 μm. To prevent electrolysis, the width of the wire 160 in the channel 170 is sufficiently narrow, so that the voltage across the wire in the channel 170 should be less than 1 volt, preferably less than 0.1 volt, at all times. The voltages used in the microfluidic system are high. A voltmeter that directly measures the voltage at the node of channel 173 through wire 160, must have a very high input impedance to be able to measure such high voltages. Such voltmeters are expensive. In addition, the manipulation of the substrate of microfluidic systems increases the possibility of contamination. Such contamination can seriously affect the voltages (and electric fields) required for the proper operation of the electrokinetic forces in the channels of the microfluidic system. To avoid such problems and costs, the wire 160 is connected to a voltage divider circuit 163, which is also formed on the surface of the substrate 178. The output of the voltage divider circuit 163 is carried by an output conductor node 161. The circuit 163 is also connected by a wire 162 to a voltage reference. The voltage divider circuit 163, shown in greater detail in FIG. 5B, was formed with the standard semiconductor manufacturing technology with resistors 165 and 166, connected as a voltage divider circuit. The wire 160 is connected to the input terminal of the circuit 163, which is one end of a linear pattern of the high strength material, such as polysilicone or alumina not contaminated or slightly contaminated. The other end of the linear pattern is connected to the reference wire 162, which is also formed on the substrate 168 and leads to an external reference voltage, presumably to ground. As shown for purposes of explanation, the voltage of the wire 160 is divided into a ratio of 10 to 1. The linear pattern is divided into a resistance 165 and a resistance 166. The resistance 165 has nine times more circuits than the resistance 166, that is, that the resistance of the resistance 165 is nine times greater than the resistance of the resistance 166. Of course, other relationships and a 1000 ratio can be used.; 1 is typical. The output wire 161, connected between the two resistors 165 and 166, leads to an external connection for a low voltage reading by a voltmeter. The cover plate will then protect the wires 160-162, the voltage divider circuit 163 and the surface of the substrate against contamination. Although the above invention has been described in some detail for purposes of clarity and understanding, it should be clear to one skilled in the art upon reading this description, that various changes in form and detail can be made without departing from the true scope. of the invention. All publications and patent documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent document had been so denoted individually.

Claims (51)

CHAPTER R VINDICATORY Having described the invention, it is considered as a novelty and, therefore, what is contained in the following is claimed

1. In a microfluidic system having a plurality of interconnected capillary channels and a plurality of electrodes at different nodes of the capillary channels to create electric fields in the capillary channels to electrokinetically move materials in a fluid through the capillary channels, a method of operation of the microfluidic system characterized in that it comprises applying voltages to the electrodes with respect to other electrodes in the system that respond to a current in the electrodes to move materials to and from the channels of the electrodes- 2.

The method according to claim 1, characterized in that the microfluidic system has at least three electrodes.

The method according to claim 2, characterized in that the step of applying voltage comprises controlling the voltage so that the current is substantially constant.

4. In a microfluidic system having a plurality of capillary channels and a plurality of electrodes at different nodes of the capillary channels to create electric fields in the capillary channels to electrolytically move materials in a fluid through the capillary channels, a method of operation of the microfluidic system characterized in that it comprises controlling over time an application of an electrical parameter between the electrodes in the system to move materials between them.

5. The method according to claim 4, characterized in that the application is controlled so that the materials move equivalently to a constant application of the electrical parameters between the electrodes in the system.

6. The method according to claim 5, characterized in that the application is controlled by varying a percentage of time in which the electrical parameter is applied.

7. The method according to claim 4, characterized in that the electrical parameter corresponds to the voltage.

8. The method according to claim 4, characterized in that the electrical parameter comprises the current.

9. The method according to claim 4, characterized in that the electrical parameter comprises the electrical energy.

10. A microfluidic system, characterized in that it comprises a plurality of capillary channels in an insulating substrate; a plurality of electrodes in different nodes of the capillary channels to create electric fields in the capillary channels to electrolytically flow materials in a fluid through the capillary channels; and at least one conductive wire on the substrate extending to the location of a capillary channel, so that a voltage can be determined at the location of the capillary channel.

The microfluidic system according to claim 10, characterized in that the conductor wire has a sufficiently small width, so that a voltage of less than 1 volt is created through the conductive wire at the location of the capillary channel.

The microfluidic system according to claim 11, characterized in that the conductive wire has a sufficiently small width, so that a voltage of less than 0.1 vplts is created through the conductive wire at the location of the capillary channel.

The microfluidic system according to claim 10, characterized in that the wire is arranged to form a voltage divider circuit on the substrate, so that the voltage received from the wire is a fraction of the voltage at the location of the capillary channel .

The microfluidic system according to claim 10, characterized in that it further comprises an insulating plate covering the substrate, the conducting wire extends towards an edge of the substrate.

15. A microfluidic system, characterized in that it comprises a substrate having a plurality of interconnected capillary channels; a plurality of electrodes in different nodes of the capillary channels to create electric fields, the capillary channels to move materials electrokinetically in a fluid through the capillary channels; a power supply connected to at least one of the electrodes, the power supply further comprises a mixing block having a first input terminal for receiving a controllable reference voltage and a second input terminal, and an output terminal; a voltage amplifier connected to the output terminal of the mixing block, the voltage amplifier has first and second output terminals, the first output terminal connected to at least one electrode; and a feedback block connected to the first output terminal of the voltage amplifier, the feedback block has an output terminal connected to the second input terminal of the mixing block, so that negative feedback is provided to stabilize the supply of Energy.

16. The microfluidic system according to claim 15, characterized in that the feedback block is connected to the first output terminal through a voltage divider circuit.

17. The microfluidic system according to claim 16, characterized in that the feedback block provides feedback to the mixing block that responds to a voltage at the first output terminal.

18. The microfluidic system according to claim 16, characterized in that the feedback block is connected to the second output terminal of the voltage amplifier, so that the feedback block generates an output voltage that responds to a current amount. which is being originated or dissipated through the first output terminal, the feedback block that provides feedback to the ^^ Mixing block responds to the amount of current that is being originated or dissipated through the first output terminal.

19. The microfluidic system according to claim 18, characterized in that the feedback block has a summing amplifier having a first input connected to the voltage divider circuit and a ^^ second input connected to the second output terminal of the 10 voltage amplifier, the summing amplifier that generates the output voltage responds to the amount of current that is being originated or dissipated through the first output terminal.

20. The microfluidic system according to claim 16, characterized in that the feedback block is connected to the second output terminal of the voltage amplifier, the feedback block that generates a first feedback voltage responds to a voltage in the first output terminal 20 and a second feedback voltage responds to a quantity of current that is being originated or dissipated through the first output terminal, the feedback block having a switch for passing the first or second feedback voltages to the block Mixed 25 responds to a control signal, so that the power supply is selectively stabilized by the voltage or feedback current.

The microfluidic system according to claim 20, characterized in that it further comprises first and second buffers connected to the feedback block, the first buffer transmits the first feedback voltage and the second buffer transmits the second feedback voltage, so that the first and second feedback voltages can be verified.

22. The microfluidic energy supply according to claim 15, characterized in that the mixing block comprises an operational amplifier connected as a summing amplifier,

23. The microfluidic power supply according to claim 22, characterized in that the operational amplifier is connected also as an integrator.

24. A power supply for connecting to at least one electrode of a microfluidic system, characterized in that it comprises a mixing block having a first input terminal for receiving a controllable reference voltage and a second input terminal, and a terminal for departure; a voltage amplifier connected to the output terminal of the mixing block, the voltage amplifier has first and second output terminals, the first output terminal connected to at least one electrode; and a feedback block connected to the first and second output terminals of the voltage amplifier and to the second input terminal of the mixing block, the feedback block generates a first feedback voltage that responds to a voltage at the first output terminal and a second feedback voltage that responds to a quantity of current that is being originated or dissipated through the first output terminal, the feedback block having a switch to pass the first or second feedback voltages to the mixing block responds to a control signal, so that the power supply is selectively stabilized at a negative feedback voltage or current.

25. The microfluidic power supply according to claim 24, characterized in that the feedback block is connected to the first output terminal of the voltage amplifier through the voltage divider circuit.

26. The microfluidic power supply according to claim 24, characterized in that the feedback block is connected to the second output terminal of the voltage amplifier., so that the feedback block generates an output voltage that responds to a quantity of current that is being originated or dissipated through the first output terminal.

27. The power supply according to claim 24, characterized in that it further comprises first and second buffers connected to the feedback block, the first buffer transmits the first feedback voltage and the second buffer transmits the second feedback voltage, so that the first and second feedback voltages can be verified.

28. The power supply according to claim 26, characterized in that the feedback block has a summing amplifier having a first input connected to the voltage divider circuit and a second input connected to the second output terminal of the voltage amplifier, the summing amplifier generates the output voltage in response to the current that is being originated or dissipated through the first output terminal.

29. The power supply according to claim 24, characterized in that the mixing block comprises an operational amplifier connected as an adder amplifier.

30. The power supply according to claim 29, characterized in that the operational amplifier is further connected as an integrator.

31. A microfluidic system, characterized in that it comprises a substrate having a plurality of interconnected capillary channels; a plurality of electrodes in different nodes of the capillary channels to create electric fields in the capillary channels to move materials electrokinetically in a fluid through the capillary channels; a plurality of power supplies connected to each of the electrodes, each of the power supplies is capable of selectively supplying a selected voltage or a selected amount of current as a source or dissipater of the connected electrodes.

32. The use of a substrate having at least one channel in which an object material is electrokinetically transported, by applying a voltage between two electrodes associated with the channel in response to a current at the electrodes.

33. The use according to claim 32, in which the substrate has a plurality of interconnected channels and associated electrodes, the target material is transported along predetermined paths that incorporate one or more of the channels by means of the application. of voltages to predetermined electrodes in response to a current in the electrodes.

34. The use of a substrate having at least one channel in which an object material is electrokinetically transported by the time-dependent controlled application of an electrical parameter between the electrodes associated with the channel.

35. Use in accordance with the claim 34, wherein the electrical parameter comprises the voltage.

36, The use of. according to claim 34, wherein the electrical parameter comprises the current.

37. Use in accordance with the claim 34, wherein the electrical parameter comprises electrical energy.

38. The use of an insulating substrate having a plurality of channels and a plurality of electrodes associated with such channels, the application of voltage to the electrodes produces electrical fields in the channels, and at least one conducting wire on the substrate extending towards the location of the channel, so that an electrical parameter can be determined at the location of the channel.

39. The use according to claim 38, wherein the conductive wire has a sufficiently small width so that a voltage of less than 1 volt, and preferably less than 0.1 volts, is created through the conductive wire at the location of the Chanel.

40. The use of an insulating substrate having a plurality of interconnected capillary channels, a plurality of electrodes in different nodes of the capillary channels to create. electric fields and capillary channels for moving materials electrokinetically in a fluid through the capillary channels, a power supply connected to, at least one of the electrodes, the power supply has a mixing block having a first input terminal to receive a reference voltage and a second input terminal, and an output terminal; a voltage amplifier connected to the output terminal of the mixing block, the voltage amplifier has first and second output terminals, the first output terminal connected to at least one electrode; and a feedback block connected to the first output terminal of the voltage amplifier, the feedback block has an output terminal connected to the second input terminal of the mixing block, so that it is provided a negative feedback to stabilize the energy supply.

41. The use according to claim 40, wherein the feedback block is also connected to the second output terminal of the voltage amplifier, the feedback block that generates a first feedback voltage responds to a voltage at the first terminal of output and a second feedback voltage responds to a quantity of current that is being originated or dissipated through the first output terminal, the feedback block has a switch to pass the first or second feedback voltage to the mixing block in response to a signal, so that the power supply is selectively stabilized by voltage or current feedback.

42. The use of a power supply for connecting to at least one electrode of a microfluidic system in which the power supply has a mixing block having a first input terminal for receiving a reference voltage and a second terminal for entrance, and an exit terminal; a voltage amplifier connected to the output terminal of the mixing block, the voltage amplifier having a first and second output terminals, the first output terminal connected to at least one electrode; and a feedback block connected to the first and second output terminals of the voltage amplifier and to the second input terminal of the mixing block, the feedback block generates a first feedback voltage in response to a voltage at the first output terminal and a second feedback voltage in response to a quantity of current that is being originated or dissipated through the first output terminal, the feedback block has a switch to pass the first or second feedback voltages to the mixing block in response to a control signal, so that the power supply is selectively stabilized in voltage or current by negative feedback.

43. The use of a microfluidic system in which a substrate has a plurality of interconnected capillary channels, a plurality of electrodes in different nodes of the capillary channels to create electric fields in the capillary channels to move materials electrokinetically in a fluid through the capillary channels, and a plurality of power supplies connected to each of the electrodes, each of the power supplies is capable of selectively supplying a selected voltage and a selected amount of current as a source or dissipator to the connected electrodes.

44. A microfluidic system, characterized in that it comprises a substrate having at least one channel in which an object material is transported electrokinetically, by means of measuring electric current and means for applying a voltage between the electrodes associated with the channel in response to the current on the electrodes.

45. The system according to claim 44, characterized in that the substrate has a plurality of interconnected channels and associated electrodes, the target material is transported along predetermined paths that incorporate one or more of the channels by means of the application of voltages to predetermined electrodes in response to a current in the electrodes,

46. The microfluidic system, characterized in that it comprises a substrate having at least one channel in which an object material is electrokinetically transported, and means for controlled application, dependent on time , of an electrical parameter between the electrodes associated with the channel.

47. The system according to claim 46, characterized in that the electrical parameter comprises the voltage,

48. The system according to claim 46, characterized in that the electrical parameter comprises the voltage.

49. The system according to claim 46, characterized in that the electrical parameter comprises the voltage.

50. A microfluidic system, characterized in that it comprises an insulating substrate having a plurality of channels and a plurality of electrodes associated with such channels, and means for applying voltages to the electrodes to generate electric fields in the channels, and at least one conductor wire on the substrate extending to the location of a channel, so that an electrical parameter can be determined at the channel location.

51. The system according to claim 50, characterized in that the conductor wire has a sufficiently small width so that a voltage of less than 1 volt, and preferably of less than 0.1 volts, is created through the conductive wire. in the location of the channel.