TW201311352A - Improved microfluidic devices useful for selective exposure of one or more sample liquids to one or more sample regions - Google Patents

Abstract

The present invention relates to improved microfluidic devices, apparatuses that include, and components of, said microfluidic devices. Further, the present invention also relates to methods involving the foregoing. The improved microfluidic devices may, in particular, include a surface acoustic wave (SAW) sensor as the sample region to which a sample liquid is exposed. The microfluidic devices of this invention provide a simple and flexible solution to one or more problems of prior art microfluidic devices, for example enabling one or more subsets of a plurality of sample regions to be exposed, such as in a selective and/or predetermined manner, to one or more sample liquids. Such functionality has particular advantages for the operation, flexibility, throughput, reliability and otherwise for the performance of the devices when in use.

Description

Improved microfluidic device useful for selectively exposing one or more liquid samples to one or more sampling zones

The present invention relates to an improved microfluidic device, an apparatus comprising the same, and a component of the microfluidic device. Further, the present invention relates to the aforementioned method. The improved microfluidic device specifically includes a surface acoustic wave (SAW) sensor as a sampling zone for exposure of the liquid sample. The microfluidic device of the present invention provides a simple and flexible solution to one or more problems with prior art microfluidic devices, such as exposing one or more subsets of a plurality of sampling regions to, for example, selective and/or predetermined manner. One or more liquid samples. This feature is especially beneficial for operation, flexibility, throughput, reliability and device performance.

Chemical and biological tests are often used to test the presence or absence of chemical or biological analytes. Testing for the presence of chemical or biological analytes in blood, food or other materials ensures safety or assists in the diagnosis of medical conditions. For example, the test can be used to confirm the acquisition of chemicals, bacteria or other analytes in a blood sample from a medical patient, laboratory samples developed for experimental purposes, food samples, and the like. In addition, chemical and biological tests can also be used to test medical conditions such as pregnancy, diabetes and various other chemical or biological symptoms that affect the patient. In another application, the research laboratory will periodically test the binding and quantified amounts or binding affinities of chemical or biological analytes. For example, to understand the binding properties of a drug candidate to its molecular target or therapeutic antibody to its antigen. The understanding of the mechanism of action of the therapeutic agent and/or its side effects can be greatly enhanced. In yet another application, analyte testing, such as drugs or explosives, can be performed for safety and law enforcement purposes. In this particular application, samples can be collected by sweat, breath or surface wiping to create particularly demanding sensitivity requirements as described by Frisk et al. (Lab Chip 8: 1504, 2006).

This test is now commonly performed using automated or semi-automated processes and/or instruments that typically pass liquid samples along a fluid path. Thus, as is generally described in such processes, a liquid sample of the presence or absence of a chemical or biological analyte (including a liquid mixture) to be detected is typically exposed to one or more sampling zones of the fluid path for storage, analysis, separation or provision. Any type of processing step for this liquid sample. As used herein, "sampling zone" means any portion of a microfluidic device that provides for storage, analysis, separation of liquid samples, or for the provision, conduct or involvement of any liquid sample. The sampling zone provides not only the function of transporting the liquid sample or the process steps. In a special case of a sampling zone involving the analysis of a liquid sample or contained components, the sampling zone is considered to be a sensor (or sensing zone), such as a sensing surface.

Unlike traditional analytical assays, such as test tube and slide clotting enzyme assays or immunoassays, the microfluidic devices of the present invention employ integrated sensors when used in assays. As used herein, "sensor" means a device that detects at least one physical change and produces a signal or includes a signal change in response to detecting a change. The manner in which the sensor detects changes may include, for example, acoustic-mechanical changes, electrochemical changes, optical changes, photoelectric changes, and the like. For example, acoustic-mechanical sensors can utilize resonant frequency, phase shift, piezoelectric properties, etc., electrochemical sensors Potential and current measurements can be utilized, and optical sensors can utilize absorption, fluorescence, self-luminescence, and evanescent waves.

One type of acoustic-mechanical sensor that has been developed for chemical or biological sensing functions is a surface acoustic wave (SAW) sensor. One example of SAW is the Love mode shear-to-horizontal surface acoustic wave (SH-SAW) sensor. The SH-SAW sensor consists of four main components: (1) a piezoelectric substrate; (2) an input digital inter-digit converter (IDT) provided on the substrate for exciting the acoustic wave according to the piezoelectric action; (3) An output IDT on the substrate for receiving the transmitted acoustic wave and utilizing the piezoelectric action to produce an electrical output; and (4) a waveguide layer disposed over the IDT for limiting the wave to the conductive layer such that the wave is input from the IDT Passed to the output IDT. The presence of one or more materials on the surface of the SH-SAW affects the wave propagation through the waveguide layer, thus assisting in the detection of specific analytes. For example, the SAW sensor can be of the layered type with the biosensing layer on the surface of the SAW device. A gold film or a ceria layer can be deposited on the surface. For example, high-affinity gold interacts with proteins, so gold can be used in conjunction with specific antibodies for antigen detection. In operation, the SAW sensor is electrically coupled to the circuit, and the circuit transmits a signal to the SAW sensor and receives a signal from the SAW sensor. Typically, the circuit includes a high frequency signal generator.

The size of microfluidic devices continues to shrink, mainly due to the need to further reduce the amount of liquid contained in the sample itself or to specifically reduce the amount of reagent required to detect a particular analyte. The microfluidic device contains a sampling zone, such as the above. Detector. Where the microfluidic device comprises a sensing region, such sensing regions can operate as little as a microliter range of liquid. The small amount of liquid needs to be introduced into the microfluidic device and supplied to the sampling area to expose the sampling area to A liquid sample (eg, an analytical liquid or a common reagent) such that (in the case of a sensing region) the sensor detects the presence or absence of an analyte in the liquid sample. Thus, such systems typically consist of a microstructured closed channel that transports fluid to and/or over one or more sampling zones that are sensing regions, such as sensing surfaces. Liquid movement can be promoted by various processes, including: mechanical micropump, electrodynamic method, electroosmosis, hydrostatic pressure difference, capillary force, centrifugal force, so-called "electrowetting" ("Creating, Transporting, Cutting, and Merging liquid Droplets by Electrowetting Based Actuation for digital Microfluidic Circuits"; Cho SK, Moon H. Kim CJ; Journal of Microelectromechanical Systems; 12(1): 70-80, 2003), or by surface acoustic wave technology suitable for transporting liquids on the surface to promote liquids Move, such as "plain jet" (Wixforth A., Scriba J. and Gauer C. in mstnews 5/02, side 42-43).

There is also a trend to continue to achieve higher yields and increased analyte complexity, such as the total number of liquid sample/sampling area exposures required for any particular survey. Complexity expectations are due to either of the following two points: (i) using a large number of nearly identical sensing regions (ie, sampling regions) to analyze a large number of different liquid samples for the same analyte; or (ii) using an appropriate amount of For different sensing zones, analyze a single (or a small number) of different analytes for some (sometimes large) different analytes, each of which is suitable for analyzing different analytes. In some applications, the scope of the survey may require two types of analysis, namely the analysis of a large number of different liquid samples for a large number of different analytes (ie, using a large number of different sensing regions). Therefore any microfluidic device for this application advantageously has a higher yield The amount and greater flexibility to handle this analysis amount and/or complexity, or the device is advantageously more reliable and/or easier to set up or operate.

In the field of biomedical and pharmaceutical research, it is easy to envisage this complexity, for example: (a) blood samples from hundreds of patients need to detect dozens of blood types, blood markers or blood-borne infections; or (b) analysis numbers Hundreds of drug candidates to combine dozens of medically relevant protein targets. In fact, in the past few years, hundreds of thousands of drug libraries have become commonplace in the pharmaceutical industry, if the number of molecules is only for the subset of thousands of human genes (and variants) that scientists can now make due to genetic changes. Analysis, it is easy to envisage the need for a combination of high-efficiency and flexible microfluidic devices.

Therefore, in this respect, particularly for microfluidic devices or applications involving analytical testing, it is advantageous to provide a microfluidic device that is flexible and/or expandable.

This scale and complexity also emphasizes the need to continue to develop smaller, more sophisticated devices for multiple trials of small (often rare or expensive) liquid samples. Many of the channels built into such microfluidic devices are typically less than a few millimeters wide or deep, sometimes less than a few hundred microns. However, such channels are typically long compared to their cross-section such that the surface area of the channel boundary contact fluid is larger than the volume of liquid contained. Therefore, the channel boundary has obvious potential surface tension or friction. Without being bound by theory, it is believed that this effect is responsible for the retention of obstacles (such as bubbles in the channel), which is a common problem with almost all types of laboratory wafer microfluidic devices.

As used herein, "obstacle" refers to any composition that does not or improperly impedes the flow of a liquid, particularly within a microfluidic device, such as a sampling zone or an internal channel. Obstructions can be solid particles (such as dust), cells or cells A bundle, a piece of material or a fiber (such as hair or textile fibers). Likewise, the obstacle can be a precipitate or crystal produced by the liquid itself. Alternatively, the barrier may be a gas, particularly a bubble or another gas or vapor, or more generally a void created by the absence of a liquid. The obstacle may also be another liquid that is the same as or different from the first liquid. Such liquid barriers are created when different liquids of different densities or hydrophobicities, such as oils and aqueous solutions, are used in the channels. Liquid barriers can also be formed from droplets of the same density and hydrophobicity but having different surface tensions with another liquid. Obstructions may be caused by microfluidic devices or internal sources of channels (eg, fragments that fall off the walls of the channel) or contaminants or material residues used to construct the channels. Alternatively, the obstacle may be caused by a microfluidic device or an external source of the channel. That is, the obstacle is introduced into the system from the liquid itself. A special form of obstacle (such as air bubbles or dust) can be caused internally or externally. For example, bubbles may be present in the liquid when they are introduced into the channel, or may be formed only as soon as the liquid is introduced into the channel. This is caused by the evaporation of the gas dissolved in the liquid or the evaporation of the liquid itself. For example, the bubbles may be formed by spontaneous degassing of the liquid, particularly if the liquid reservoir is maintained at a different temperature than the sensing unit, and as the liquid flows from the reservoir to the sensing unit, the change in temperature of the liquid affects the amount of carrier gas of the liquid.

As with certain microfluidic devices and/or applications, air (especially air bubbles), dust, and/or other may be introduced when the secondary unit, part or the entire device is operated by exposure of liquid, sampling area, passage or other components to the air. obstacle. This occurs, for example, if the liquid connection changes, or particularly after the portion of the device, the secondary unit, or the component is operated, the sampling zone (eg, the sensing zone/surface) is exposed, exchanged, modified, or otherwise interfered. Typically, such sensitive components are periodically replaced, cleaned, or repaired (eg, before each day of use, or even before each experiment), so such actions often inevitably introduce obstacles or air into the device.

If higher assay throughput and flexibility are required (as described above), microfluidic devices can be designed accordingly, such as sub-units with independent and separable sections, each with several sampling zones and channels to provide a more scalable design Or more practical producers. For example, multiple smaller wafers may provide multiple sensing regions (eg, SAW sensing regions) that are easier, more reliable, and less expensive, each wafer containing less sensing area than providing a single large wafer containing the total number of sensing regions. A microfluidic device designed on a sub-unit basis offers many other advantages, including replacing the non-functional portion of the device by replacing only the secondary unit containing the non-functional portion, without replacing the large parts of the device. However, based solely on the law of probability, with the complexity and scale of such sub-unit-based microfluidic devices (eg, having multiple subunits), replacing (or otherwise operating) any one or more of the microfluidic devices Units will become more and more likely and frequent.

As the complexity of microfluidic devices increases, a particular way of forming air, bubbles or other pores in channels, sampling zones, or elsewhere in the microfluidic device becomes of particular interest, especially if the device is designed on a subunit basis. That is, when the liquid is first introduced into the emptied or substantially emptied portion of the device, the secondary unit (eg, opening, servicing the device components, or after the liquid or internal features of the device are exposed to air). If the liquid is introduced into the dry or in particular if a partially dried microfluidic device or any of its component sections or subunits is introduced, bubbles or other voids may be formed or air may be trapped, in particular If the flow rate or pattern of liquid flow into or through the microfluidic device (especially into or through the contained channel or sampling zone) is not controlled. In the relevant case, if a portion of the microfluidic device (e.g., a sampling block) does not fill the liquid in the proper sequence or order, bubbles or other voids may be formed or trapped.

Various solutions are known in the prior art to reduce the possibility of bubble formation or pore formation or the initial introduction of a microfluidic device (for example, as described herein and in the patent application EP 10171508.4). A more robust approach to this problem is to actually remove bubbles, air or pores. More physically, it is practical and simple to remove any other fluid (eg, gas (eg, air) or even other improper liquid) from a particular portion of the microfluidic device (eg, the sampling unit or sub-unit of the device) without affecting Or introducing an improper fluid into another specific portion of the microfluidic device.

In this regard, in particular, microfluidic devices or applications that are prone to this condition, provide microfluidic devices to quickly and simply remove bubbles, pores (or, more generally, any other fluid, such as gas, air, or even other improper Solutions to liquids or other obstacles are advantageous. As such, providing a solution to control the filling of liquid within the device may simplify, assist, and/or more reliably prepare a suitable device, or in particular, prepare one or more sampling zones, such as a SAW sensing zone.

If an obstacle such as a void (e.g., a bubble) remains in the microfluidic device, the obstacle greatly reduces the process performance that the device should perform, such as any detection assay function, particularly when the system is quantitatively detected. This sensitivity to obstacles, such as air bubbles, is common in almost all sensing techniques used to detect the presence or absence of chemical or biological analytes. For example, because of SAW The sensor is sensitive to changes in the quality of its sensing surface, so obstacles that remain on the surface of the SAW sensing area and are detected unexpectedly, whether it is a solid obstacle (such as dust particles) or a gaseous obstacle (such as a bubble) Both will affect the surface-mass and greatly affect the propagation of sound waves through the waveguide layer, resulting in incorrect or improper signals. Obstructions (e.g., air bubbles) may also remain elsewhere in the fluid flow features of the microfluidic device, such as microfluidic channels, and still adversely affect the correct or optimal performance of the microfluidic device. For example, bubbles remaining in the fluid system before or after the sensing zone will limit the channel cross-section, with some liquid flow systems that will significantly reduce the flow rate of liquid through the channel and across the surface of the SAW sensing zone. In particular, when the obstacle completely restricts the passage and blocks the flow of the fluid, the decrease in the flow rate greatly affects the predetermined or expected performance of the SAW sensing area, and can confirm its own effects, such as reducing sensitivity, stability, accuracy, reliability, and/or Or detect the reproducibility of the test. If the obstacle remains in a microfluidic "laboratory wafer" microfluidic device based on other detection techniques, a sensing surface (eg, a surface plasmon resonance (SPR) based sensing unit) is also used. A similar problem can occur.

The application EP 10171508.4, which is hereby incorporated by reference, describes a microfluidic device having a characteristic structural composition which reduces the presence of air bubbles and other obstacles in the sensing unit, the sensing unit comprising a SAW sense Measuring area. The device also includes features that assist in visually confirming bubbles or obstructions, causing subsequent removal and removal of bubbles or obstacles. The multi-channel SAW-based microfluidic device described herein presents the same liquid sample flowing sequentially through all of the sensing regions.

The Biacore 3000 instrument from GE Healthcare provides a liquid sample for selective flow through one or more detection flow cells from a total of four detection flow channels, each of which contains an SPR sensing area (see Figure A, taken from Biacore 3000 Instrument Manual, "Figures 2 to 8 of GE Healthcare"). Selective fluid flow is achieved by using various channels and individual valves, with individual valves acting as shut-off valves to regulate the flow of liquid only to the desired or predetermined detection flow channels. Valve designs suitable for this application are described in WO 02/36485.

US 2010/9191660 describes a channel switching system comprising two microvalves: a first "stop" valve (which can be opened and closed) and a second "water retaining" valve (which is operable to block fluid flow using surface tension) .

No. 5,230,866 describes a microfluidic device that uses a capillary stop junction to reintroduce the flow into different sampling zones of the device.

WO 2008/097559 describes the use of oil droplets in a microfluidic device to control the flow of liquid, for example in combination with an inlet valve and an outlet valve to sequentially fill the micropores (see, for example, Fig. 12 therein).

WO 2007/084425 describes automated microfluidic wafers and assay systems. By selectively operating the inlet valve, the distribution (selection) valve, and the fluid pump, various fluid flow pattern combinations from different reservoirs and along different channels can be achieved (see, for example, Figure 1 therein).

US 2010/0028986 describes a reaction vessel plate and a reaction treatment device comprising a switching valve and a plurality of seals joined together by a fluid channel in series (see, for example, Figure 1A) or in parallel (see, for example, Figure 14A) Reaction vessel.

WO 2009/068201 describes a micro gas analyzer formed on a microchip that includes various separation columns and detectors that can be individually addressed by using a specific junction and shut-off valve configuration. The gas is sampled from the downstream gas stream using a plurality of junctions and shut-off valves.

WO 2009/003520 describes a dual valve configuration for a liquid chromatography analyzer in which the first or second fluid path can be selectively addressed depending on the respective settings of the first and second switching valves.

EP 1 586 894 describes a gas chromatography layer analyzer with a plurality of separation columns. With the input selection valve and the output selector valve, the gas flow can be passed through any individual separation column, with each selection valve having an output (or input) connected to each separation column.

WO 01/57520 describes an apparatus for performing analytical measurements and methods for assessing molecular interactions. The apparatus includes a sample feed system set, each set being switchable to an analytical flow path having a detector using at least one switching valve, wherein each sample feed system is comprised of a plurality of sampling loops, which can be "successively and mutually Independently address each sampling loop.

Despite these developments, microfluidic devices (especially those including sensors such as SAW sensors) still have some drawbacks, including limited yield, flexibility, efficiency, and/or parallelization, and even if prior art provides various solutions. Ways to redirect the flow or reduce the frequency of obstacles in the microfluidic device, but especially for high-yield subunit-based designers who are often subject to interference or disturbances due to improper function and/or performance, including by introducing micro Interference or disturbance caused by an obstacle such as a bubble generated by a fluid device or a microfluidic device. Therefore, on the one hand, it is provided by an alternative solution. The microfluidic device is modified to redirect the flow. This solution provides one or more advantages over existing solutions when applied specifically to multi-channel or multi-component microfluidic devices (ie, including multiple sampling zones). For example, (i) may increase throughput, flexibility, and/or efficiency of the device (eg, reduce liquid sample consumption per channel/assay); and/or (ii) may simplify removal of obstacles or fills in the microfluidic device The procedure of the empty microfluidic device, and/or can be performed in a more robust or reliable manner. Such procedures enable the device to be assembled, ready to operate and/or operate with better performance, which not only increases flexibility, expandability and/or throughput, but also reduces the likelihood of retaining obstacles. Individual identified parts, sub-units or components (eg individual sampling areas or a set of sampling areas) may be removed from any identified obstacles without affecting other parts of the device, sub-units or components (eg sampling areas), eg preparation Good or in action. On the other hand, new microfluidic devices have been developed, for example based on SAW sensors, such as sensitivity, accuracy, stability, reliability, ease of use, robustness and/or reproducibility. Improve performance. These improvements are particularly useful when microfluidic devices are used to detect assays.

The present invention as claimed, defined or recited herein may solve one or more of the above problems, overcome one or more disadvantages of the prior art solutions, and/or provide an alternative to the prior art.

In general terms, the main aspects of the invention are illustrated below.

In a first aspect, the invention relates to a microfluidic device for a liquid, the microfluidic device comprising: a plurality of sampling zones, the sampling zone being connectable in series via one or more connecting channels; a selector valve having a sampling input and a plurality of outputs, each valve output being connectable to an input of a sampling zone via a liquid passage; and a second (output) selection valve having a sampling output and a plurality of Inputs, each valve input can be connected to the output of the sampling zone via a liquid channel. In a second aspect, the invention relates to a method of exposing a plurality of liquid samples to a plurality of sampling zones contained in a microfluidic device of the invention, the method comprising the steps of: setting at least a first (input) and a a second (output) selection valve for providing liquid continuity from the sample input to the sample output via the first set of sampling zones; introducing a first liquid sample into the sample input for circulation and exposure of the first liquid sample to the first set a sampling zone; at least setting the first (input) and the second (output) selection valves to provide liquid continuity from the sampling input to the sampling output via the second set of sampling zones; and introducing the second liquid sample into the sampling input, The second liquid sample is circulated and exposed to the second set of sampling zones.

In another aspect, the invention relates to a microfluidic device comprising the invention Equipment and/or apparatus for carrying out the method of the invention. In other aspects, the invention relates to a method of detecting a microfluidic device of the invention, a method of preparing a microfluidic device, a flow cell for a microfluidic device, and a computer program product for use in the apparatus or method of the invention.

The invention and in particular the non-limiting aspects and/or embodiments of the invention are generally described as follows.

In a first aspect, the invention relates to a microfluidic device for a liquid, the microfluidic device comprising (cf. Fig. 1): a plurality of sampling zones (1a...1n), the sampling zone being via one or more The connecting channels (2a...2m) are connected in series to the liquid continuity; the first (input) selection valve (3), the first selection valve has a sampling input (4) and a plurality of outputs (5a...5x), each A valve output is connectable to the input (6) of the sampling zone via a liquid channel (7); and a second (output) selection valve (8) having a sampled output (9) and a plurality of inputs (10a.. .10y), each valve input can be connected to the output (11) of the sampling zone via a liquid channel (12).

The microfluidic device provides greater flexibility in providing a liquid path, thereby providing various routes for liquid sample flow, and exposing various individual sampling zones depending on the settings of the first (input) selection valve and the second (output) selection valve (or a subset of adjacent sampling areas). For example, using the settings shown in Figure 1, the liquid sample introduced into the input (4) of the selector valve (3) can only be exposed to Sampling areas (1b) and (1...). Not limited to theory, the incompressibility of liquids in other sampling areas and liquid connections prevents liquid samples from flowing into other sampling areas (or, if empty, the capillary action of the liquid at the junction and the limited compression efficiency of the gas) Effectively provide "stop flow" junction). If the second (output) selector valve (8) is then set to 埠 (10b), the liquid sample can be exposed only to the sampling zone (1b). Alternatively, if the first (input) selection valve (3) is set to 埠 (5a) and the second (output) selection valve (8) is then set to 埠 (10y), the liquid sample can pass and be exposed to the overall plurality of samples. Zones (1a) to (1n). This flexibility can be used, for example, to prepare a plurality of sensing regions (eg, SAW sensing regions) to detect the same analyte (using valve settings (5a) and (10y) to expose all sensing regions to a common liquid sample for preparation) Then, each liquid sample is sequentially exposed to a sensing area, and then the individual liquid samples in the presence of the analyte are inspected using appropriate settings of the selection valves (3) and (8). Alternatively, in other aspects, the flexibility of the microfluidic device of the present invention can be used, for example, to prepare a plurality of sensing regions (eg, SAW sensing regions), each sensing region detecting a different analyte (using a particular valve setting to cause each sensing The zone is sequentially exposed to a specific liquid sample for the preparation of a particular sensing zone to detect a particular analyte), followed by a single common liquid sample in which all of the different analytes are present (using valve settings (5a) and (10y) to give sense of all The test area is exposed to a liquid sample).

The present invention not only provides a more flexible microfluidic device as described above, but also saves cost; for example, a particular process should require only one or a small number of sampling zones in terms of volume/consumption of a liquid sample or other desired reagent. Unused sampling areas can be excluded from the liquid path, saving the total amount of liquid sample (or other liquid reagent) required. Correspondingly, do not allow unwanted sampling areas (example Exposure to liquid samples, such as expensive biosensors, allows the sampling area to be used in other processes and provides an economic advantage. In other aspects, the invention is superior to the prior art. For example, although the sampling area is connected in series (2a) to (2m) in series with liquid continuity, the appropriate selection of two selection valves can flush improper liquids (such as previous process use or leave) and fill new liquids. Individual sampling areas do not flow into other sampling areas. In addition, if bubbles, pores, or other obstacles are present in the sampling area, it is easy to "wash out" from the sampling area and discard, and does not enter another sampling area.

In some embodiments, the devices of the present invention are used (e.g., beneficial or particularly suitable) for liquids having a lower pressure than HLPC. For example, the device can be used with liquids having a pressure of less than about 500 kPa, such as a liquid having a pressure of 10 to 500 kPa. In an alternate embodiment, the device is not used (eg, not beneficial or particularly unsuitable) for a liquid having a pressure greater than about 1, 2, 5, 10, 50, or 100 kPa.

The microfluidic device of the present invention can be used in any number of different liquid types. For example, the liquid can be hydrophilic or hydrophobic. Liquids suitable for use with microfluidic devices include aqueous liquids such as aqueous analyte solutions. Suitable liquids or mixtures of different liquids, such as aqueous liquid mixtures (or solutions thereof), organic solvent mixtures (or solutions thereof), hydrophilic and hydrophobic liquid or suspension emulsions in hydrophilic or hydrophobic liquids. In a particular embodiment, the liquid system comprises an aqueous liquid of the analyte selected from one or more of the group consisting of proteins, peptides, small molecules, sugars, carbohydrates and glycoproteins, nucleic acids, cells, cell debris, Lipids, vesicles, membranes and membrane fragments, cell extracts, food extracts, drugs/drugs Metabolites and explosives and mixtures and/or compositions of the above.

The "connectable" components of the microfluidic device of the present invention can be directly connected (as shown in Figure 1) or have additional valves (such as selector valves, shut-off valves, or switching valves, as shown in Figures 5 through 10). The additional valve redirects the flow to, for example, a set of at least one (eg, two) possible inputs or outputs from the sampling zone to the selector valve connection. In particular embodiments, such connectable components are connected through, via, or with an application valve that provides connectability and/or creates fluid connectivity.

It will be understood by those of ordinary skill in the art that the selection valve of the apparatus of the present invention can be provided by any suitable valve assembly, for example, from at least one (common) enthalpy to (or from) some other defect. Preferably, the valve type is a rotary selector valve, such as that manufactured by Rheodyne or Vici. In an alternate embodiment, a suitable valve assembly that provides a similar function is a manifold (ie, a shared input port that is divided into a plurality of output ports), one or more (preferably all) of the manifolds have a shut-off valve on the output port, Isolation or stop valve. This selection valve based on a manifold/shutdown valve is particularly beneficial for certain devices of the present invention, such as those requiring high fluid production or higher speed analysts.

The microfluidic device of the present invention comprises one or more connecting channels in two adjacent sampling intervals. In some embodiments, at least one connecting channel of adjacent sampling intervals (within the same secondary unit) is directly connected to the pair of sampling regions. For example, this connection channel does not include a shut-off valve, an isolation valve, or a stop valve.

In other embodiments of the microfluidic device of the present invention, each sampling zone has an input, the input being connectable to a particular output of the first (input) selection valve; and/or each sampling zone has an output, the output being connectable to the Second Out) Select the specific input of the valve. In this embodiment, the various components can be configured such that (ie, the input/output and valve configurations are configured to be connected) the liquid can flow in any of: (a) via any single sampling zone; or (b) via at least two The sampling zone (at most all sampling zones), wherein the flow depends at least on the setting of the first (input) valve and/or the second (output) selector valve.

In an alternate embodiment of the apparatus, not every sampling zone has an input (and/or output) that is connectable to a particular output (or input) of each selector valve. For example, as shown in Figure 1(c), a subset of the two sampling regions have such inputs and outputs that are addressable and expose the fluid to the pair of sampling regions.

The microfluidic device of the present invention can include a first (input) selection valve and/or a second (output) selection valve, each of which includes at least one output or input that is not connectable to the sampling zone. This type of disconnection helps to flush, wash and/or transport waste through the various selector valves and associated parts of the unit without passing through any sampling area.

The microfluidic device of the present invention may further comprise a liquid drive source. The liquid drive source is preferably located upstream of the first (input) selector valve. Any suitable drive source for the liquid includes a positive displacement pump or a speed pump. In a preferred embodiment, the liquid drive source is a syringe pump. Other suitable liquid drive sources include peristaltic pumps or piezoelectric pumps. The provision of a liquid drive source can utilize the microfluidic devices of the present invention to assist and control fluid flow and processing.

In a particular embodiment of the microfluidic device, the sampling zone comprises a sensing zone, a sampling coil, a reaction chamber, a vessel or a separation column. The microfluidic device of the present invention preferably includes at least one sampling zone (eg, a plurality or all of the sampling zones), the sampling zone including a sensing zone, such as a biosensor, and/or The sensing region (or all sensing regions) is selected from the group consisting of: SPR sensors, electrochemical sensors, optical sensors (eg, fluorescent sensors or self-luminous sensors), acoustics A sensor (such as a QCM sensor or SAW sensor). Each sampling zone of the microfluidic device preferably includes a SAW sensor.

In a particular embodiment, at least one biosensor of the device (eg, a SAW sensor) is adapted to allow the detection primitive to incorporate the sensor surface, or a detection primitive having a bonding surface. Preferably, the detection unit is selected from the group consisting of an antibody, a nucleic acid (eg, DNA, RNA or PNA), a protein, a peptide, an aptamer, a cell, a charged molecule, a membrane, a vesicle, a chemical or an electrochemical The receptor is more preferably a monoclonal antibody. Methods for modifying the sensing region and incorporating detection motifs are known to those skilled in the art, including those described by Gronewold (Aptamers and Biosensors, "Nucleic Acid and Peptide Aptamer" by Ed Mayer, Humana Press, New York. ).

In other particular embodiments, at least one sampling zone (preferably all) of the device comprises a SAW sensor. The surface area of the SAW sensor is preferably selected from the group consisting of about 20 square millimeters, 10 square millimeters, 7.5 square millimeters, 5 square millimeters, 2.5 square millimeters, 2 square millimeters, 1 square millimeter, or preferably about 4 square millimeters to 8 square millimeters, for example, about 6.0 square millimeters to 6.8 square millimeters.

In another embodiment, the microfluidic device of the present invention is characterized by one or more of the following: For at least one adjacent sampling zone pair (preferably for all adjacent pairs), the connecting channel (eg, (2a) of Figure 1) separates the first sampling zone The output and the input of the second sampling zone, the connecting channel: (a) having a volume of from about 0.01 microliters to about 100 microliters, the volume being, for example, selected from the group consisting of about 0.02, 0.04, 0.05, 0.1, 0.25, 0.5, 1, 10, 20 And a group consisting of 50 microliters, preferably about 0.04 microliters; and/or (b) having a cross-sectional area of about 0.01 square millimeters to 5 square millimeters, the area being selected, for example, from about 0.02, 0.04, 0.05, 0.1, a group of 0.25, 0.5, 1 and 3 square millimeters, preferably about 0.04 square millimeters; and/or With respect to at least one liquid passage (e.g., (7) of Figure 1) (preferably for all such passages), (i) the liquid volume of the liquid passage is from about 1 microliter to about 200 microliters, the volume For example, selected from the group consisting of about 2, 4, 5, 10, 15, 20, 50, and 100 microliters, preferably about 7 microliters; and/or (ii) the cross-sectional area of the liquid channel is about 0.005 From square millimeters to about 5 square millimeters, the area is, for example, selected from the group consisting of about 0.01, 0.02, 0.04, 0.05, 0.1, 0.25, 0.5, and 1 square millimeter, preferably about 0.012 square millimeters; and/or For at least one sampling zone (eg, (1a) of Figure 1) (preferably for all sampling zones), (x) the channel cross-sectional area above the sampling zone is from about 0.1 square millimeters to about 3 square millimeters. The area is, for example, selected from the group consisting of about 0.2, 0.3, 0.4, 0.5, 0.75, 1 and 2 square millimeters, preferably about 0.3 square millimeters; and/or (y) the liquid volume of each of the sensing regions is From about 0.25 microliters to about 30 microliters, the volume is, for example, selected from the group consisting of about 0.5, 1.0, 1.25, 1.5, 1.75, 2.0, 5, 10, 15 and 20 microliters, preferably about 3.0 microliters; And/or The total liquid volume of at least one fluid subunit of the microfluidic device is about 3 Increasingly to about 500 microliters, the volume being, for example, selected from the group consisting of about 5, 10, 15, 20, 50, 100, 150, 250, and 400 microliters, preferably about 13 microliters, wherein "Fluid subunit" means the portion of the device that passes from the output of the first (input) selector valve via two adjacent sampling zones and their associated connecting channels, but does not include any from the second sampling zone or liquid channel to the second (output) The output of the valve is selected (for example, the total capacity of (7), (1a), (2a), and (1b) in Fig. 1).

In some embodiments of the invention, the at least one connecting channel has a cross-sectional aspect ratio of from about 1:0.1 to about 1:10, and the aspect ratio is, for example, selected from about 1:0.5, 1:0.75, 1:1, 1: a group consisting of 1.5 and 1:2; and/or a channel cross-sectional aspect ratio above the at least one sampling zone is selected from a width to a vertical dimension aspect ratio approximately in the middle of the sampling zone, the aspect ratio being selected from about 2: A group consisting of 1, 5: 1, 7.5: 1, 10: 1, 15: 1, and 20: 1, preferably about 10.5:1 or 7.5:1. In a preferred embodiment, the cross-section of the channel above the sampling zone is larger than the other portion at a certain traverse of the channel, preferably at a distance of about the middle, larger than the side of the channel, such that the channel has a house shape Cross section (for example, as described in patent application EP10171508.4 in the application).

The various input connections to and/or from the sampling area can be provided and configured in any suitable manner. For example (refer to Figure 1(a)), for at least one sampling area (preferably at least two, preferably all sampling areas), the relevant connecting channel and the input of the sampling area (or the output of the sampling area) Liquid continuity through the T-connection (13); and/or (see Figure 1(b)), for at least one sampling zone (preferably at least two, preferably all sampling zones) The connection channel and the input of this sampling area (or the output of this sampling area) are liquid continuous through the independent connection of each connection channel (14a) to the sampling area and the input of the sampling area (or the output of the sampling area) (14b) .

In a particular embodiment of the microfluidic device of the present invention, for at least two sampling regions (preferably all sampling regions), the associated inputs and outputs of the sampling regions are fluidly connected via separate connections to the respective sampling regions. . For example, refer to the inputs and outputs (214i/o) and (314i/o) of FIGS. 2 and 3, respectively; and/or at least one sampling area (preferably at least two, preferably all sampling areas). And/or at least partially comprised of independent sub-units of the microfluidic device; and/or at least two sampling zones and their associated connecting channels together comprise flow channels. Preferably, the flow channel comprises a flow boundary substantially as shown in (21) of Figure 2 or (31) of Figure 3, and/or comprises associated inputs and outputs substantially as configured in the figures.

In another preferred embodiment, the microfluidic device of the present invention comprises at least two sampling zones and associated connecting channels, the sampling zone and its associated connecting channels together comprising a flow channel; the flow cell comprising independent subunits of the microfluidic device, When contacting another unit of the microfluidic device, the individual subunits are adapted to form the sampling regions and their associated connecting channels (e.g., (22) and (32) as shown generally in Figures 2 and 3, respectively). In a particularly preferred embodiment, the other sub-unit sensing surfaces of the microfluidic device, such as those comprising at least two SAW sensors, when so contacted, each sampling region of the flow cell comprises a SAW sensor.

In a particular embodiment of the invention comprising all aspects of the flow channel, the flow channel is adapted to introduce liquid into the sampling zone (eg, a SAW sensor) near. The design, orientation and/or size of the flow channel may be adapted to assist in the introduction, such as reducing the volume of liquid containing the analyte liquid or reducing the likelihood of introducing or retaining bubbles or other obstacles near the sensing surface. If the invention comprises flow channels, the flow channels may preferably be adapted to determine the interaction of the power rate parameters. The flow cell may be made of a biocompatible material, preferably selected from the group consisting of polyacetal, polymethyl methacrylate, polyvinyl chloride, and injection molded thermoplastic materials such as polystyrene or acrylonitrile butadiene styrene, but Without limitation, and/or the flow channel may be made of a flexible and/or (appropriate) transparent material, such as a decane. Such materials provide the proper transparency of the flow cell so that obstructions detected or identified in the flow cell can be observed. As is known to those skilled in the art, the flexible alkane flow tank can be made from a naphthenic rubber, for example, using 2 parts of a naphthenic elastomer kit from various suppliers such as Dow Corning, Wacker Chemie, or Quantum Silicones. The size of the flow channel can be adapted to determine the rate of dynamics of the molecular interaction, i.e., in this embodiment, the flow characteristics should permit maintaining the overall solution concentration of the analyte ligand at or very close to the sensing surface. In some embodiments, the flow cell is typically or preferably disclosed in WO 2009/153189, EP 10171508.4 in the same application, or Community Design Regulations 001789785-0001 through -0009.

In a preferred embodiment of all aspects of the invention, the flow channel includes a flow boundary and/or a connecting channel, and the flow boundary and/or the connecting channel can form a liquid sample flow path across the plurality of sampling regions (eg, SAW sensing) And/or providing the sampling area to be arranged in a tiled column, wherein the flow cell as shown, the two sampling zones of the series fluid continuity are actually similar to each other (eg As parallel to each other). This flow cell configuration and design is particularly advantageous for wafer-based sensors, such as the plurality of sampling zone SAW sensors, including columns or arrays on a single wafer. Alternatively, the fluid input/output of a particular sampling zone may occur at each end of the sampling zone (as shown in Figure 3) or may occur within the connecting channel to form a partial flow cell (as shown in Figure 2). In some embodiments, the flow channel provides a cross-sectional area of the sampling zone across the sampling zone (eg, the SAW sensing zone) that is larger (eg, wider) than the cross-sectional area of the connecting channel. For example, the cross-sectional area and/or width across the sampling zone is from about 2 to about 10 times, such as about 3, 4, 5, or 7 times the cross-sectional area and/or width of the connecting channel. In a related embodiment, the flow channel provides a path length of fluid flowing through the sampling zone (eg, the SAW sensing zone) that is from about 1.5 times to about 10 times longer than the width of the fluid flowing through the sampling zone, such as about 2, 3, 5 or 5 inches long. 7 times. In other embodiments, the flow channel comprises a vertical dimension, wherein the vertical dimension is higher at one point across the channel than at the other, preferably at about the middle, the vertical dimension is higher than the vertical dimension at the side of the channel, such that The passage is in the shape of a roof with a roof, as detailed in EP10171508.4 in the application.

As noted above, microfluidic devices that include discrete or sub-units that are advantageous for design expansion, construction, and maintenance are susceptible to problems with filling/rinsing fluids to reduce the risk of improper fluids (including bubbles/pores of gases or other liquids). From one device sub-unit to another. Therefore, the present invention is particularly suitable for microfluidic devices comprising independent subunits, for example comprising separate or separable flow channels and sensing surfaces, wherein the secondary units are interconnected to form a multi-channel microfluidic device that is selectively addressable and exposed And/or fill/flush a subset of individual sampling zones. In this embodiment, a portion or sub-unit of the device may be separated for repair, cleaning or assembly, which may result in loss of liquid, drying of the portion or sub-unit, and/or introduction of a gas (eg, air), bubbles or pores. Therefore, in some embodiments, the microfluidic device of the present invention is a multi-channel device comprising: 2, 3, 4, 5, 6, 7, 8, 9, 12, 15, 16, 18, 24, Some sampling zones of 25, 48, 96, 10 to 19, 20 to 29, 30 to 49, and 50 to 100 groups, and/or all of the plurality of sampling zones are composed of two or more independent flow channels (each The flow cell contains a subset of sampling zones), wherein the individual flow cells can be connected via interconnecting channels as shown in Figure 4a (41).

In a particular embodiment, the flow cell stored in the microfluidic device of the present invention comprises a plurality of sampling zones selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. Preferably, the microfluidic device comprises from 2 to about 5 flow channels; and/or preferably, the flow channel of the microfluidic device comprises liquid continuity substantially as shown in FIG. It will be understood by those of ordinary skill in the art that although FIG. 4 specifically depicts the flow channel as shown in previous FIG. 2 (and in other embodiments) (and having a flow boundary (21)), a similar FIG. 3 can be utilized. The flow channel of the flow boundary configuration shown in (31) achieves liquid continuity similar to that shown in Fig. 4. Thus, in a particular embodiment, the microfluidic device of the present invention comprises liquid continuity substantially as shown in Figure 4 and comprises at least two flow channels, each flow cell comprising a flow substantially as shown in Figure 3 (31) boundary. As shown in Figure 4(a), the input (I) and output (O) selection valve settings expose the liquid sample to the sampling zones A3, A4 and to the B1 and B2 via the interconnecting channels (41). In figure 4(b), The output selector valve (O) is set such that the liquid sample is only exposed to the sampling zones A3, A4, and the liquid sample from the output of A4 flows directly to the output valve (O) and flows into the flow cell B without passing through the interconnecting passage (41).

As described above, during certain applications of certain apparatus embodiments of the present invention (as shown in FIG. 4), the flow tank A is separated/removed (eg, a new application/experiment is expected to change the sensing area, or cleaned or performed After other inspection or repair work, the interior of the flow cell/sampling zone may become very dry or dry, and/or air, bubbles or other voids may be introduced into the system. The liquid is then reintroduced into the flow tank A at the time of recombination/reinsertion to introduce air or one or more bubbles or liquid mixture (which has been left in the interconnecting passage (41)) and air (from the flow tank A) into the flow tank B. . This will result in a runaway wetting flow tank B and/or an internal sampling zone (eg, a SAW sensor). Uncontrolled wetting can cause air/bubbles (or other obstacles) to become trapped, resulting in unreliable, inaccurate, and/or (at least partially) non-functional sampling zones (eg, as in the European Patent Application No. EP10171508.4 in the application). No.). Thus, in some embodiments of the microfluidic device of the present invention, at least one of the switching valves also has liquid continuity in the device. In some embodiments, the switching valve configuration causes one or more sampling zones to be filled and/or flushed with liquid such that any improper liquid/air can flow into the device output and not into any other sampling zone. While the additional features are particularly advantageous for embodiments of the present invention that include separate flow channels, it will be apparent to those skilled in the art that the "fill/flush" feature provided by the switching valve can also be used in other device embodiments. Therefore, referring to Fig. 5 (corresponding to the schematic diagram of the liquid continuity shown in Fig. 6), when the liquid flows into the subunit A (for example, after opening and reorganizing the subunit A), the subunit A With the switching valve (51) set as shown in Fig. 5(a), any residual/inappropriate liquid or air will be discharged from the sampling area of the secondary unit A via the 埠(iii) of the (output) selection valve (O). Therefore, residual/inappropriate liquid or air is not introduced into the sampling zone of the secondary unit B. Subsequently, once the sampling zone and the liquid channel of the secondary unit A have been properly filled, flushed or prepared with the liquid, the switching valve (51) is set to the position shown in Figure 5(b) to provide the last sampling from the secondary unit A. The liquid continuity of the input of the zone to the input of the first sampling zone of sub-unit B. In addition, as can be seen from the setting of the switching valve (51) of Fig. 5(a), the respective sampling regions of the secondary unit A or B can be addressed without affecting the function of the secondary unit A, or filled with liquid/ Flush all subunits B. Therefore, the switching valve can provide additional functions of "fill/flush" without affecting the positioning of each sampling zone (or adjacent sampling) by appropriately setting the first (input) selection valve (I) and the second (output) selection valve (O). Block) and the flexibility to expose the sampling area to liquid samples.

Accordingly, a particular embodiment of the microfluidic device of the present invention further comprises (see Figure 5) at least one switching valve (51), the switching valve being connectable to at least (i) the output of the first sampling zone (52); (ii) The input of the second sampling zone (53); and (iii) the input of the second (output) selection valve (54), such that the input/output and valve configurations are configured such that the flow is available from the first sampling zone The output is switched to an input of the second sampling zone or an input of a second (output) selection valve; wherein the switching valve is preferably further connected to (iv) the output of the first (input) selection valve (55), such input to the The flow of the two sampling zones can be switched from the output of the first (input) selector valve or from the output of the first sampling zone. The microfluidic device embodiment preferably comprises substantially as shown in FIG. Or the liquid continuity shown in FIG. 6; and/or the microfluidic device preferably comprises at least two flow channels, each flow cell comprising substantially as shown in (21) of FIG. 2 or (31) of FIG. Flow boundary.

As will be apparent to those skilled in the art from the disclosure of the present invention, FIGS. 5 and 6 show a switching valve as a 2×2 switching valve (also referred to as an “injection valve”) of four turns, but using a 3× such as six. 2 Switching valves, but using only two pairs of 埠, so that the n × 2 switching valve function is used as a 2 × 2 switching valve, can also achieve similar functions. In fact, six-inch 3x2 switching valves are often more readily available and less costly, and various application embodiments of the present invention specifically contemplate the use of such valves.

In Figures 5 and 6, when the switching valve is in the "fill/flush" position (as shown in Figures 5(a) and 6(b) respectively), the flow is from the first set of sampling zones ( In the second figure, the flow cell "A" is flown to the second (output) selector valve (O) of the device and does not flow to the input of the sampling zone of the flow cell B. When in the alternate position of the switching valve (as shown in Figures 5(b) and 6(a) respectively), one sampling area in the first group of sampling areas (A) (in this case, the last sampling area) The output of the liquid does not flow to the second (output) selector valve (O), but flows through the interconnecting channels (52), (53) to another sampling zone in the second set of sampling zones (B) (in In this example, for the input of the first sampling zone, a plurality of sampling zones are provided in series with liquid continuity.

In the particular embodiment illustrated in Figure 5 (and corresponding liquid continuity as shown in Figure 6), the first and second sampling zones are adjacent and represent the last sampling zone and flow cell of flow cell A, respectively. The first sampling area of B. Therefore, in an embodiment of the microfluidic device of the present invention, the first sampling area is adjacent to the second sampling area, for example, the first sampling area is the first of the first flow channels. The latter sampling zone is the first (i.e., first) sampling zone of the second (e.g., adjacent) flow cell.

In an alternative embodiment of the microfluidic device of the present invention, the switching valve arrangement is such that the output of the "first" sampling zone is coupled to the input of a non-adjacent "second" sampling zone via a bridge connector. Therefore, referring to Fig. 7 (corresponding to the schematic diagram of the liquid continuity shown in Fig. 8), the sampling regions of 埠(i) and (ii) connected to the switching valve (71) are non-adjacent from the subunits A and B. Sampling area. Configuring the switching valve (71) and interconnecting passages (74) accordingly provides for a more flexible sampling zone that may be configured to expose the sampling zone to a liquid sample, and in particular to expose non-adjacent sampling zones to liquid samples. For example, when the switching valve (71) is set as shown in Fig. 7(a), the liquid sample cannot flow into the (72b) via the bridge passage (72a), but the input selection valve (I) and the output selection valve can be appropriately set. (O) to address all of the individual sampling zones (or adjacent pairs of sampling zones) to provide the same effective flexibility as the embodiment shown in FIG. However, after the selection valve is set as shown in Fig. 7(b), the liquid can flow through the bridge channel, exposing the non-adjacent sampling area to the liquid sample.

Figures 8(a) through 8(d) illustrate exposure of a liquid sample to a number of different possible patterns of one or more sampling zones by appropriately setting two selector valves and switching valves, including exposure to an eighth b) Figure to the non-adjacent sampling area shown in Figure 8(d). In light of the disclosure herein, one of ordinary skill in the art can readily envision various other exposure patterns that may be utilized in conjunction with the present embodiment and how to extend additional sampling zones, flow channels, and/or switching valves.

Accordingly, a particular embodiment of the microfluidic device of the present invention further comprises (see Figure 7) at least one switching valve (71), the switching valve being connectable to at least: (i) An output of the first sampling zone; (ii) an input of the second sampling zone; and (iii) an input of the second (output) selection valve (73); wherein the first sampling zone is not adjacent to the second sampling zone, and A sampling zone is connectable to the switching valve (71) via a bridge connector (72) such that the flow (ie, input/output and valve configuration configuration) can be switched from the output of the first sampling zone (72a) to non-adjacent ( Second) the input of the sampling zone (72b) or the input of the second (output) selection valve (73). In this embodiment, the series liquid continuity of the plurality of sampling zones is provided by interconnecting channels (74).

As described above, the switching valve and bridge connector configurations of embodiments of the present invention provide some advantages for the utility of the microfluidic device. For example, particularly when the total number of sampling zones is increased and/or the (two or more) subunits of the sampling zone are used, device flexibility can be greatly increased because the liquid sample can be exposed to the sampling zone, which does not have to be (directly) contiguous Another sampling area. Accordingly, some apparatus embodiments of the present invention include a plurality of first sampling zones, a plurality of second sampling zones, the switching valve, and the bridging channels, wherein the components are in fluid continuity, such (input/output and valve construction) The liquid is configured such that the connection can be made according to the switching valve setting: flowing through the last sampling area of the plurality of first sampling areas to the initial sampling area of the plurality of second sampling areas, or from the plurality of first through the bridge channel The intermediate (first) sampling zone of the sampling zone flows to the (second) sampling zone of the plurality of second sampling zones, wherein the (second) sampling zone does not abut the intermediate (first) sampling zone. The microfluidic device embodiment preferably comprises fluid continuity substantially as shown in Figure 7 or Figure 8; and/or the microfluidic device preferably comprises at least two flow channels, each flow cell comprising substantially as in Figure 2 The flow shown in (21) or (31) of Figure 3 Dynamic boundary.

It will be understood by those skilled in the art that depending on the relative position of the non-adjacent sampling regions, in embodiments of the invention, there may be different patterns for exposing the liquid sample to a plurality of sampling regions, and the relative positioning may be designed to achieve better or expected picture of. Thus, in some embodiments, the microfluidic device of the present invention comprises a plurality (N) of first and/or second sampling regions, wherein N is selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, A group consisting of 10, 11 and 12; the bridge channel connects the selector valve and the intermediate sampling zone positioned at N-1 or lower. In this embodiment, N is preferably selected from the group consisting of 2, 4, 6, and 8, and N-1 is selected from the group consisting of 1, 2, 3, and 4.

As noted above, the present invention can encompass two different functions of the switching valve: "fill/flush" and "bridge", both of which provide advantages or benefits to the device of the present invention, including those described herein, such as flexibility and ease of use. . In a particular embodiment of the invention, two functions can be combined in the same device to provide a microfluidic device that combines advantages, namely, devices that allow for "filling/flushing" and addressing and exposing liquid samples to non-adjacent sampling regions.

Therefore, in some embodiments (refer to Figure 9), the microfluidic device of the present invention further comprises a second switching valve, wherein: The (first) switching valve (91) is configured to switch the flow from the output of the first sampling zone (90) to the input of the second (output) selection valve (92) or the second sampling zone (94), the second sampling The zone is adjacent to the first sampling zone; The second switching valve (93) is configured to switch flow from the output of the intermediate (first) sampling zone (95) to a second (output) selection valve (92) or a non-adjacent (second) sampling zone (96) )input of; Each switching valve is preferably further connected to at least one output of the first (input) selection valve (97a/b) such that the flow input to each of the second sampling zones is (ie, the input/output and valve configuration are configured) The output of the first (input) selection valve is switched or from the output of each of the first sampling zones.

The microfluidic device embodiment preferably comprises liquid continuity substantially as shown in Figure 9; and/or the microfluidic device preferably comprises at least two flow channels, each flow cell comprising (21) substantially as in Figure 2 Or the flow boundary shown in (31) of Fig. 3.

The combination of the "fill/flush" and "bridge" functions provides the advantage of the present invention comprising the particular synergistic effect of the microfluidic devices incorporated herein. For example, as can be seen from Figure 8, when the selector valve is set to "bridge" (as shown in Figure 8(b)), it is still possible to pass parallel flow through the Z-shaped interconnect channel (81) and via selection The valve (83) passes through the bridge connector (82a/b). Depending on the relative liquid flow resistance of the two liquid paths (via (81) or via (82a/b)), in some cases the parallel flow through (81) may be quite a few (or in other cases parallel) The flow may be insignificant, so the embodiment shown in Figure 8 still retains its utility). In contrast, the corresponding liquid path (Fig. 9) in the device embodiment with the "fill/flush" and "bridge" functions is examined, by appropriately setting the "fill/flush" selection valve (91) (eg In the setting shown in Fig. 9(b), it is impossible to pass the parallel flow through the connecting passage of the connected two flow tanks (98a/b), so in this embodiment, the "fill/flush" switching valve (91) is provided. The function can enhance the "bridge" function provided by the switching valve (93). The general practitioner understands that by properly setting the two selector valves (input (I) and output (O) selector valves) and two switching valves (filling/flushing) Washing (91) and bridging (93) switching valves) various liquid sample patterns (including non-adjacent sampling areas) exposed to the sampling area, and how to properly set the same four valves for filling, rinsing or ready to use Flow tank A or B.

As noted above, any switching valve illustrated as a 2x2 valve can be any suitable multi-turn switching valve (also referred to as an "injection valve"), such as an nx2 switching valve, particularly a 3x2 switching valve.

In the above embodiment (substantially as shown in Fig. 9), in the case of using two four-inch 2×2 switching (injection) valves, the "fill/flush" and "bridge" functions are switched by two independent switches. Valves (91) and (93) are provided. In an alternate embodiment of the microfluidic device of the present invention, the "fill/flush" and "bridge" functions can be combined with a single switching valve (e.g., a 3 x 2 switching valve) having a switching capability greater than 2 x 2. Thus, in some embodiments (see Figure 10), the microfluidic device includes a selector valve (111) that is connectable to at least: (i) an output of the first sampling zone (117); (ii) a second sampling zone (115) input; and (iii) second (output) selection valve (114) input, such that the input/output and valve configuration are configured to provide a flow that can be switched from the output of the first sampling zone to the second An input to the sampling zone or an input of a second (output) selection valve; wherein the switching valve is preferably further coupled to (iv) an output of the first (input) selection valve (116), such that the liquid is input to the second sampling zone The flow can be switched from the output of the first (input) selection valve or from the output of the sampling zone. In this embodiment, the selection valve may be further connected to at least one of: (v) an output of the third sampling zone (112); and (vi) an input of the fourth sampling zone (113), wherein the first and the first The two sampling zones are adjacent to each other, and the third and fourth sampling zones are not adjacent to each other, such that the input/output and valve configuration configurations are: The flow may be switched from the output of the third sampling zone (112) to the input of the fourth (non-adjacent) sampling zone (113) or the input of the second (output) selection valve (114); input to the second sampling zone The flow of (115) may be switched from the output of the first (input) selection valve (116) or from the output of the first (adjacent) sampling zone (117); and input to the fourth sampling zone (113) The flow may be switched from the output of the first (input) selection valve (116) or from the output of the third (non-adjacent) sampling zone (112). Preferably, the microfluidic device comprises liquid continuity substantially as shown in FIG. 10; and/or the microfluidic device preferably comprises at least two flow channels, each flow cell comprising (21) or substantially as shown in FIG. The flow boundary shown in (31) of Fig. 3 .

A person skilled in the art can see from Fig. 10(a) that although some of the specific selector valve outputs may be "connectable" to two sampling zone inputs, the outputs of the first (input) selection valve (116) are "connectable". Input to the sampling zone, wherein the particular sampling zone is selected or addressed by the setting of the switching valve (111). Accordingly, for a particular input, each input of the second (output) selection valve (114) is also "connectable" to the output of the sampling zone depending on the setting of the switching valve (111). In Figure 10(a), although the illustration has 8 turns, the two selector valves contain only 7 outputs (or inputs), since the eighth embodiment is not used in the illustrated embodiment. In other embodiments, however, the crucible can be used as an output (or input) to provide a waste, wash or rinse function.

One of ordinary skill in the art will appreciate that in any embodiment of the invention, a selection valve can be employed that includes more than the actual fluid continuity for the microfluidic device. In addition, any embodiment of the microfluidic device of the present invention may further add additional sampling zones, flow cell subunits, and associated valves and fluid passages. And expand, enlarge or expand.

In a particular embodiment, the microfluidic device of the present invention further includes at least one sensor, feature, adapter, or other member to control and/or inspect the first (input) selection valve, the second (output) selection The setting of the valve and / or at least one switching valve (if provided). The member preferably controls and/or inspects all valve positions of the device; and/or the member preferably controls and/or inspects the operation of the liquid drive source (if present).

Such control/inspection members are particularly useful in embodiments of microfluidic devices that include one, two or more switching valves as in the present invention. For example, in some different valve setting embodiments, the liquid of any (common) input of the introduction device (eg, the input of the first (input) selection valve) may not continuously and freely flow out of the (common) output of the device (eg, second (output) selects the output of the valve). Such a combination of settings can damage the device (or even potentially pose a potential hazard to the user), especially if the liquid drive source is actively introduced (eg under pressure) with the pump, such a combination of settings should preferably be avoided. Suitable control and inspection components are known to those skilled in the art (e.g., using a programmable logic controller or a suitably programmed personal computer (PC) and/or electromechanical valve, such as a solenoid or stepper or servo motor driver). With appropriate control components (usually a specific computer program that controls various valve settings but does not allow for some potential damage or "end" to the valve setting combination), the control/inspection member is only allowed to provide continuous and free flow of liquid into and out of the device. Settings. In an alternative embodiment of the invention that does not include the control and/or inspection member, the user can control and/or check the valve settings prior to introducing the liquid into the device.

In other embodiments, the microfluidic device of the present invention further comprises one or more of the features disclosed in the patent application EP 10171508.4. For example, the apparatus can include: (a) a sensing surface that, when mounted, is oriented at an angle between horizontal and vertical (but not equal to horizontal and vertical), wherein the fluid used to provide the fluid sample Preferably, the 埠 is set lower than the fluid enthalpy for removing the fluid sample from the sensing surface such that the flow direction of the fluid sample is substantially upward; (b) the cross-section of the channel above the sampling zone is perpendicular to the vertical dimension of the channel. a large, preferably vertical dimension at about the middle is greater than the vertical dimension of the side of the channel, such that the channel has a house-shaped cross-section; and/or (c) a portion of the device that covers the sensing surface is sufficiently transparent to operate in general Detecting bubbles or other obstacles remaining in the sensor (eg, in the channel or on the sensing surface, preferably on the sensing region), wherein the sidewall of the channel contacting the sensing surface is Made up of deformed materials. In some embodiments, one or more of the features will be further characterized by the patent application EP 10171508.4, which is hereby incorporated by reference.

The microfluidic device of the present invention provides flexibility in process throughput and/or complexity, and the process can be used to process one or more liquid samples after exposure to one or more sampling zones, the device being useful in various aspects of the invention Process.

Thus, in a second aspect, the invention is directed to a method of exposing a plurality of liquid samples to a plurality of sampling zones contained in a microfluidic device of the invention, the method comprising the steps of: At least setting a first (input) and a second (output) selection valve of the apparatus to provide liquid continuity from the sampling input to the sampling output via the first set of sampling zones; introducing the first liquid sample into the sampling input for the Flowing and exposing the first liquid sample to the first set of sampling zones; at least setting the first (input) and the second (output) selection valves to provide continuous flow of liquid from the sampling input to the sampling output via the second set of sampling zones And introducing a second liquid sample into the sampling input for the second liquid sample to circulate and be exposed to the second set of sampling regions.

In a method embodiment employing a microfluidic device comprising at least one switching valve, the method is further characterized in that the one (or two) setting step further comprises setting the switching valve.

In some method embodiments of the invention, the first and second sets of sampling zones differ by at least one additional sampling zone. The first and second sets of sampling zones preferably differ from all of the individual sampling zones; and/or each set of sampling zones is less than a total number of sampling zones. In a particular embodiment, each set of sampling zones is an individual sampling zone. Thus, in some embodiments, the method is a method of selectively exposing a plurality of liquid samples to a plurality of sampling zones contained in the microfluidic device of the present invention.

The above method of the present invention provides a method of exposing a two liquid sample to a second (set) sampling zone (using the microfluidic device of the present invention). However, some method embodiments further include repeatedly performing a pair of setting and introducing steps to expose at least one additional liquid sample to at least one other sampling zone (or subset of sampling zones). By repeating, for example, repeating the pair of method steps 2, 3, 4. About 5 or about 10 times, multiple liquid samples can be exposed to multiple (multiple sets) of sampling zones. In fact, in a preferred method embodiment, such steps can be repeated until at least one liquid sample has been exposed to each of the plurality of sampling zones contained in the microfluidic device.

In some applications or processes that are experienced or used in a liquid sample, device, or sampling zone, a single liquid sample may be predetermined or expected to be exposed to multiple sampling zones (eg, exposed to all sampling zones within the device). Thus in a particular embodiment, the method further comprises the steps of: At least setting a first (input) and a second (output) selection valve to provide liquid continuity from the sampling input to the sampled output via a plurality of (eg, all) sampling regions of the plurality of sampling regions; A common liquid sample is introduced into the sampling input for the common liquid sample to circulate and be exposed to the sampling regions of the plurality of sampling regions.

One of ordinary skill in the art will recognize that the additional step of exposing a common liquid sample to such sampling zones of a plurality of sampling zones can be performed before and/or after the setting/introduction steps for any particular liquid sample. For example, the common liquid may be first exposed to all sampling zones, and the sampling zone is a sensing zone (eg, a SAW sensor) to prepare all of the sensing zones to detect the same specific analyte, and the individual liquid samples are then exposed to the individual sensing zones. To detect the presence of the same analyte in different sampling areas. In an alternative example, individual sensing regions may be first exposed to individual liquid samples to prepare individual sensing regions to detect different analytes, and common liquid samples are then exposed to all sensing regions to detect whether a single common liquid sample is detected. There are a variety of different analytes. These additional steps of exposing the common liquid sample to the sampling zones of the plurality of sampling zones Execution before or after other steps of the method of the invention will depend on the particular application or device use or the process being performed. The microfluidic devices and methods of the present invention offer the possibility of this flexibility.

Thus, the method of the invention can be applied to detect: a plurality of analytes in individual liquid samples; and/or individual analytes in a plurality of liquid samples. In some embodiments, at least two sampling regions (preferably all sampling regions of the device) are adapted to detect the presence or absence of at least one analyte in the liquid sample. In an embodiment of the method of the present invention for detecting an analyte of a liquid sample, preferably, at least one of the sampling regions of the sampling regions is a biosensor. Preferably, all of the sampling zones of the sampling zones are biosensors and/or SAW sensors.

In some method embodiments for detecting, at least two of the sensing regions are each adapted to perform the above method of exposing the two liquid samples to the two (group) liquid samples to detect the presence or absence of different analytes, and then The method of exposing the common liquid to the sampling zones is performed to detect the presence or absence of at least two analytes in the common liquid sample. In an alternative embodiment, at least two of the sampling regions are each adapted to first detect the presence or absence of the same analyte (by performing the method of exposing the common liquid to the sampling regions as described above), and then by performing the above A method of exposing a two liquid sample to two (sets) of different sampling zones to detect the presence or absence of the analyte in at least two liquid samples.

Any method of the present invention may further comprise the step of controlling and/or inspecting a first (input) selection valve, a second (output) selection valve, and/or at least one switching valve (if provided). Control and / or inspection steps are better This is done prior to the steps of introducing the liquid sample into the microfluidic device, such as before the liquid drive source is activated. The control and/or inspection steps may be performed by an operator of the device, or may utilize a selective feature of the device that incorporates or is adapted to assist and/or perform such control and/or inspection steps.

In a related aspect, the present invention relates to a method for detecting the presence or absence of a plurality of analytes in a liquid sample using the microfluidic device of the present invention, the microfluidic device comprising a plurality of sensing regions (eg, SAW sensors) The method comprises the steps of: exposing at least two liquid samples to two different sets of sensing regions to prepare the different sensing regions for different analyte detection (eg, by performing the above method); exposing the common liquid In the sensing regions (eg, by performing the above method); and by detecting changes in properties of each sensing region (or sensing region group) to detect the presence or absence (or absence) of each analyte in the common liquid sample .

In some embodiments of this method, the step of exposing a particular liquid sample to a different sensing region (or sensing region group) is repeated until the sensing region is ready for detecting all of the plurality of analytes.

In an alternative to this aspect, the present invention is also directed to a method of detecting the presence or absence of an analyte in a plurality of liquid samples using the microfluidic device of the present invention, the microfluidic device comprising a plurality of sensing regions (eg, SAW) a sensor), the method comprising the steps of: exposing a common liquid to the sensing regions to prepare the plurality of sensing regions for detection of the analyte (eg, by performing the method described above); Exposing at least two liquid samples to two (group) different sensing regions (eg, by performing the above method); and detecting each liquid sample by measuring changes in properties of each sensing region (or sensing region group) Whether or not the analyte is present (or missing).

In some embodiments of the method, the exposing of the particular liquid sample and associated detection steps are repeated until all of the plurality of liquid samples have been exposed to different sensing regions (or sensing regions).

One of ordinary skill in the art will appreciate that in certain embodiments, one or more of the above detection methods can be performed prior to other detection processes that also require complexity or throughput.

In another aspect, the invention relates to a method of preparing a microfluidic device of the invention, wherein the device comprises at least a secondary unit and at least one switching valve having the filling/rinsing function described above, at least one of the secondary units Having been operated in advance, the method comprises the steps of: setting a first (input) selection valve, a second (output) selection valve, and a switching valve such that a liquid sample flows through the previously operated secondary unit to a second (output) selection valve And another unit that does not flow into the device; and introduces a liquid sample into the device to prepare the pre-operated subunit.

In a particular embodiment, the method further comprises the steps of: resetting the valve to cause the liquid sample to flow through at least one other sub-unit of the apparatus to the second (output) selection valve, and not to the pre-operated sub-unit; A liquid sample is introduced into the apparatus to prepare at least one other subunit of the apparatus.

In some embodiments, this method is before or after the set/import step Further comprising the steps of: setting a first (input) selection valve, a second (output) selection valve, and a switching valve to cause fluid to flow through the entire operating sub-unit and/or the entire fluid system of the device, followed by introduction of a gas (eg, air) ) to discharge and/or dry any liquid sample remaining in the operated sub-unit and/or device.

In some embodiments, each unit comprises a flow channel and a sensing surface as described herein, the sensing surface comprising a plurality of sensing regions, such as a SAW sensor.

The microfluidic devices of the present invention may be incorporated or the methods of the present invention may be practiced as part of a device. Thus, a third aspect of the invention pertains to apparatus comprising the microfluidic device of the invention and/or apparatus for (e.g., beneficial or particularly suitable) practice of the method of the invention. Preferably, the device includes or uses a microfluidic device that is a multi-channel biosensor, such as a multi-channel SAW sensing device.

In some embodiments, the apparatus of the present invention further comprises an autosampler. The term "autosampler" is well known to those of ordinary skill in the art and includes mechanical systems that address and remove (preferably individual) specific liquid samples from a plurality of liquid samples. Typically, a plurality of liquid samples are represented as an array of containers (eg, tubes) or within a microplate, and the autosampler uses a position-controlled sampling tube or needle that can be moved three-dimensionally relative to the array of containers (eg, using Cartesian electromechanical Positioning system) allows each liquid sample in the array to be positioned in 2 dimensions and then sampled toward the 3D moving tube/needle. Manufacturers suitable for autosamplers are well known, including Spark Holland.

In other embodiments, the apparatus of the present invention further includes a computer program product. The computer program product is preferably adapted to control the microfluidic device of the present invention, a method suitable for practicing the present invention, and/or the computer program product includes instructions to perform or control the steps of the method of the present invention. The computer program product may include a data carrier, and the carrier includes data representing a computer program available to the device. For example, the computer program product can be rewritable programmable read only memory (EPROM), random access memory (RAM), read only memory (ROM), hard disk, solid state disk (SSD), universal serial The bus (USB) flash drive or CD/DVD, or the computer program product can be an external personal computer, a programmable logic controller (PLC) or a motherboard, and in each case, contains information indicating that it is suitable for the computer program. The computer program product may include or further include an authorization key (for example, provided by the authorization label or as individual information, or may store or utilize a USB transmitter), the license key is unlocked or the pre-loaded or individually supplied computer program is allowed to start (complete) The function, or authorization key, can be an instruction (such as a web page URL and/or a login/password) that describes how to obtain, load, or download a computer program.

In yet another aspect, the invention is directed to a flow channel as described, defined or claimed herein. Preferably, the flow channel is for (or beneficial or particularly suitable for) the microfluidic device of the present invention, for example having a flow boundary substantially as shown in Figure 21 of Figure 2 or (31) of Figure 3.

In still another aspect, the invention is also directed to a computer program product described, defined or claimed herein. Preferably, the computer program product is for (or beneficial or particularly suitable for) the microfluidic device of the invention or the method of practicing the invention.

It should be understood that the general practitioner may, after following the teachings herein, The teachings are applied to a particular problem or environment and include variations or additional features of the invention. Representative examples of apparatus, devices, and other aspects of the invention, and representative methods of use or processes thereof, are not to be construed as limiting the invention to such representative examples.

All references, patents, and publications referred to herein are hereby incorporated by reference in their entirety.

1-4, 1a-1n‧‧‧ sampling area

2a-2n‧‧‧ connection channel

3,8‧‧‧Selection valve

4, 6‧‧‧ input

5a-5x‧‧‧ Output埠

7, 12‧‧‧ channels

9, 11‧‧‧ output

10a-10y‧‧‧Input埠

13‧‧‧T-connection

14a‧‧‧Connected channel

14b‧‧‧Sampling area

21‧‧‧ border

22a-22m‧‧‧ connection channel

31‧‧‧ border

32‧‧‧Connecting channel

41‧‧‧Interconnection channel

51‧‧‧Switching valve

52, 53‧‧‧ Connection channel

54, 55‧‧‧Selection valve

71‧‧‧Switching valve

72‧‧‧Bridge connector

72a-b‧‧‧Bridge connector/sampling area

73‧‧‧Selection valve

74‧‧‧Interconnecting channels

81‧‧‧Connecting channel

82, 82a-b‧‧‧Bridge connector

83‧‧‧Selection valve

90, 94-96‧‧‧ sampling area

91, 93‧‧‧Switching valve

92, 97a-b‧‧‧Selection valve

98a-b‧‧‧Flow tank

111‧‧‧Switching valve

112, 113‧‧‧ sampling area

114, 116‧‧‧Select valve

115, 117‧‧‧ sampling area

214i, 314i‧‧ input

214o, 314o‧‧‧ output

I‧‧‧ input selection valve

O‧‧‧Output selector valve

Schematic representation: Figure A (previous technique) illustrates the flow of liquid sample through two flow channels ("FC") of a Biacore 3000 instrument. The symbols "○" and "●" represent the valves that open and close, respectively. Valves and channels that are not used for other flow path configurations are not included. Excerpted from the "Biacore 3000 Instrument Manual" published by GE Healthcare.

Figure 1 illustrates an embodiment of the invention comprising: four sampling zones (1a to 1n) connected in series via a connecting channel (2a to 2m); a first (input) selection valve (3), first The selector valve has a common input (4) and a series of output ports (5a to 5x), each output port being connected to the input (6) of the sampling zone via the liquid channel (7); and a second (output) selection valve (8), The second selector valve has a common output (9) and a series of input ports (10a to 10y), each input port being connected to the output (11) of the sampling zone via a liquid channel (12). Figures 1(a) through 1(b) are enlarged diagrams showing possible liquid continuity and connections between the sampling zone, the input channel and the input (or output) of the sampling zone. Figure 1(c) A related embodiment of the invention is shown wherein adjacent pairs of sampling regions (relative to individual sampling regions of the prior embodiments) are coupled to first (input) and second (output) selection valves.

Figure 2 illustrates an embodiment of the invention comprising four sampling zones (1 to 4) of liquid continuity in series via connecting channels (22a to 22m), formed in a flow channel having a flow boundary (21) In each case, there are independent inputs (214i) and outputs (214o) connected to the respective sampling zones; and input (I) and output (O) selection valves that are connected to the respective sampling zones via the liquid channel. Output connection.

Figure 3 illustrates a related embodiment shown in Figure 2, which also includes a flow channel, but with an alternate pattern of flow boundaries (31).

Figure 4 illustrates another embodiment of the present invention comprising two flow channels A, B (each substantially as shown in Figure 2), the flow channels being connectable in series via the interconnecting channels (41) for fluid continuity. Fig. 4(a) illustrates that the liquid is caused to flow and the sampling areas A3 to B2 are exposed via the interconnection passage (41) by appropriately setting the selection valve (I) and the selection valve (O). Figure 4(b) illustrates an alternative setting of the selector valve (O) that selectively exposes the sampling zones A3, A4 to the liquid sample introduced into the microfluidic device.

Figure 5 illustrates an embodiment of the invention comprising two subsets (A and B) of two sampling zones, and further comprising a switching valve (51), which may be in accordance with the "fill/flush" embodiment of the present invention connection. The fifth (a) diagram illustrates that the liquid flows into the sensing area A1 along the set flow of the selection valve (I) and flows along the set flow of the selection valve (O) from the sensing area A2. The liquid sample selectively flows from the selection valve (I) and exposes the sampling areas A1, A2, and passes through the switching valve (51) Set to be discarded via the selector valve (O), thereby filling/rinsing a subset of the sampling zone A without flowing liquid into any of the sampling zones of the subset B. Figure 5(b) illustrates an alternative setting of the switching valve (51) and the selection valve (O) that selectively exposes not only the sampling zones A1, A2 to the liquid sample introduced into the microfluidic device, but also the sampling zone B1. B2 flows through the switching valve (51) through the liquid to the input of the sampling zone B1, and is discarded from the output of B2 via the selector valve (O).

Figure 6 illustrates another embodiment of the present invention comprising two flow channels A, B (each substantially as shown in Figure 2), the flow channels being connectable in series via a switching valve for liquid continuity, the switching valve being in accordance with the present invention The "fill/flush" embodiment is connected. The liquid continuity of Fig. 6 is similar to that of Fig. 5 except that the sampling units of Fig. 6 contain flow channels (A, B) of four sampling zones. Figure 6(a) illustrates the selection valve (I), switching valve, and selector valve (O) settings to expose the liquid sample to all eight sampling zones A1 through A4 and B1 through B4. Figure 6(b) illustrates the selection valve (I), switching valve, and selector valve (O) settings such that the liquid sample is only exposed to the sampling zone A4 and is discarded by "filling/rinsing" A4.

Figure 7 illustrates an embodiment of the invention comprising two subsets (A and B) of two sampling zones, and further comprising a switching valve (71) that can be coupled in accordance with the "bridge" embodiment of the present invention. Figure 7(a) illustrates the input selection valve (I), switching valve, and output selection valve (O) settings to expose the liquid sample to all four sampling zones A1 to A2 and B1 to B2, through which the liquid flows through the interconnecting channels ( 74). Figure 7(b) illustrates the switching valve setting to cause the flow to "bridge" the output from A1 to the non-adjacent sampling area B2 via the bridge connector (72a/b).

Figure 8 illustrates another embodiment of the present invention comprising two flow channels A, B (each substantially as shown in Figure 2), the flow channels being connectable in series via a switching valve The fluid is connected and the switching valve can be connected in accordance with the "bridge" embodiment of the present invention. The liquid continuity of Fig. 8 is similar to that of Fig. 7, except that the sampling unit of Fig. 8 includes flow channels (A, B) of four sampling areas, and the "bridge" connector (82) bridges four sampling areas. The second sampling area of each group. Figure 8(a) illustrates the selection valve (I), switching valve and selector valve (O) settings exposing the liquid sample to all eight sampling zones A1 to A4 and B1 to B4. Figure 8(b) illustrates a switching valve in a "bridged" position for providing liquid continuity from the output of A2 to the input of B3, leaving the liquid sample exposed to sampling zones A1, A2, B3, B4. Figure 8(c) illustrates the selection valve (I), switching valve and selector valve (O) settings for exposing the liquid sample to the sampling zones A2 to A4 and B1 to B3. Figure 8(d) illustrates a switching valve in a "bridged" position for providing liquid continuity from the output of A2 to the input of B3, leaving the liquid sample exposed only to the two sampling zones.

Figure 9 illustrates yet another embodiment of the present invention, comprising two flow channels A, B (each substantially as shown in Figure 2) and having two switching valves, the switching valve (91) being configured to "fill/flush" The mode operates and the other switching valve (93) operates in a "bridged" mode. Figure 9(a) illustrates the valve setting to expose the liquid sample to all eight sampling zones. Figure 9(b) illustrates two switching valves instead of setting the liquid flow to expose the sampling zones A1, A2, B3, B4.

Figure 10 illustrates yet another embodiment of the present invention, comprising two flow channels A, B (each substantially as shown in Figure 2) and having a 3 x 2 switching valve (111), the switching valve being further operable in accordance with the present invention An embodiment is connected. Figure 10(a) illustrates the selection valve (I), selection valve (O), and switching valve (111) settings to "fill/flush" the liquid sample via the sampling zone of flow cell A. Figure 10(b) shows the selection Valve selection (I) and selection valve (O) are set to "fill/flush" the liquid sample via the sampling zone of flow cell B. Figure 10(c) illustrates the selection valve (I), selection valve (O), and switching valve (111) settings to expose the liquid sample to all of the sampling zones A1 through B4. Figure 10(d) illustrates the switching valve (111) setting to expose the liquid sample to the sampling zones A1, A2, B3, B4.

1a-1n‧‧‧Sampling area

2a-2n‧‧‧ connection channel

3,8‧‧‧Selection valve

4, 6‧‧‧ input

5a-5x‧‧‧ Output埠

7, 12‧‧‧ channels

9, 11‧‧‧ output

10a-10y‧‧‧Input埠

I‧‧‧ input selection valve

O‧‧‧Output selector valve

Claims (21)

A microfluidic device for a liquid, the microfluidic device comprising: a plurality of sampling zones, wherein the sampling zones are connectable in series via at least one connecting channel; a first (input) selection valve, the first selector valve Having a sampling input and a plurality of outputs, each valve output is connectable to an input of a sampling zone via a liquid passage; and a second (output) selection valve having a sampling output and a plurality of inputs Each valve input can be coupled to an output of a sampling zone via a liquid passage. The microfluidic device of claim 1, wherein: each sampling zone has an input connectable to a particular output of the first (input) selection valve; and/or each sampling zone has an output, The output can be coupled to a particular input of the second (output) selector valve. The microfluidic device of claim 2, wherein the plurality of components of the microfluidic device are configured such that liquid can flow in any of: (a) via any single sampling zone; or (b) via at least two sampling zones Where the flow depends at least on the setting of the first (input) valve and/or the second (output) selector valve. The microfluidic device of any one of claims 1 to 3, wherein the at least one sampling zone comprises a surface acoustic wave (SAW) sensor; wherein a surface area of the SAW sensor is preferably about 4 square millimeters to 8 square millimeters, for example about 6 square millimeters or 6.8 square millimeters. The microfluidic device of any one of claims 1 to 4, wherein, for at least two sampling regions, a plurality of associated inputs and outputs of the at least two sampling regions are individually connected to the respective at least two sampling regions a sampling zone for liquid continuity; and/or at least one sampling zone comprising and/or at least partially comprised of a separate subunit of the microfluidic device; and/or at least two sampling zones and a plurality of at least two sampling zones The associated connecting channels collectively comprise a flow channel; wherein the flow channel preferably comprises a plurality of flow boundaries substantially as shown in (21) of Figure 2 or (31) of Figure 3. The microfluidic device of claim 5, wherein: the at least two sampling regions and the plurality of associated connecting channels of the at least two sampling regions together comprise a flow channel; and the flow channel comprises a separate sub-unit of the microfluidic device, When contacting another unit of the microfluidic device, the independent subunit is adapted to form a plurality of associated connecting channels of the sampling regions and the sampling regions. The microfluidic device of claim 6, wherein the flow channel comprises Free sampling zones of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 groups, wherein the microfluidic device preferably comprises 2 From about 5 such flow channels; and/or wherein the microfluidic device preferably comprises liquid continuity substantially as shown in FIG. The microfluidic device according to any one of claims 1 to 7, further comprising at least one switching valve connectable to at least (i) an output of a first sampling zone; (ii) a second sampling An input of the zone; (iii) an input of the second (output) selection valve; such flow may be switched from the output of the first sampling zone to the input or the second (output) of the second sampling zone Selecting the input of the valve; wherein the switching valve is preferably further coupled to (iv) an output of the first (input) selector valve; the flow thus input to the second sampling zone is selectable from the first (input) The output of the valve is either switched from the output of the first sampling zone; and/or wherein the microfluidic device preferably comprises liquid continuity substantially as shown in Figure 5 or Figure 6; and/or wherein the microfluidic Preferably, the apparatus includes at least two flow channels, each flow cell comprising a plurality of flow boundaries substantially as shown in (21) of Figure 2 or (31) of Figure 3. The microfluidic device of claim 8, wherein the first sampling zone is not Adjacent to the second sampling zone, and connectable to a switching valve via a plurality of bridge connectors; such that the flow can be switched from the output of the first sampling zone to the input of the non-adjacent (second) sampling zone or The second (output) selects the input of the valve. The microfluidic device of claim 9, comprising a plurality of first sampling zones, a plurality of second sampling zones, the switching valve and the bridge connectors, wherein the components are in liquid continuity, so the switching valve is regarded as Depending on the setting, the liquid may flow through the last sampling zone of the plurality of first sampling zones to the initial sampling zone of the plurality of second sampling zones; or from the plurality of first sampling zones via a plurality of bridging channels An intermediate (first) sampling zone flows to a (second) sampling zone of the plurality of second sampling zones, wherein the (second) sampling zone does not abut the intermediate (first) sampling zone; wherein the microfluidic device Preferably, the fluid continuity is substantially as shown in FIG. 7 or FIG. 8; and/or wherein the microfluidic device preferably comprises at least two flow channels, each flow cell comprising (21) substantially as in FIG. 2 or A plurality of flow boundaries shown in (31) of Fig. 3 . The microfluidic device of claim 8 further comprising a second switching valve, wherein: the (first) switching valve is configured to direct the flow from the first sampling zone Switching to the input of the second (output) selection valve or a second sampling zone adjacent to the first sampling zone; and the second switching valve configured to direct flow from an intermediate (first The output of the sampling zone is switched to an input of the second (output) selection valve or a non-adjacent (second) sampling zone; wherein each switching valve is preferably further connected to the first (input) selection valve At least one output, such that the flow input to each of the second sampling zones is switchable from the output of the first (input) selection valve or from the output of each of the first sampling zones; and/or wherein the microfluidic device is Preferably, the liquid continuity is substantially as shown in Figure 9; and/or wherein the microfluidic device preferably comprises at least two flow channels, each flow cell comprising substantially as in (21) or Figure 3 of Figure 2 ( 31) Multiple flow boundaries as shown. The microfluidic device of claim 8, wherein the selection valve is further connected to at least one of: (v) an output of a third sampling zone, in addition to the connectors (i) to (iv) And (vi) an input of a fourth sampling area, wherein the first sampling area and the second sampling area are adjacent to each other, the third sampling area and the fourth sampling area are not adjacent to each other, such that: The flow of the output of the third sampling zone is configured to switch to the input of the fourth (non-adjacent) sampling zone or the input of the second (output) selection valve; the flow input to the second sampling zone Configure to select from the first (input) The output of the selected valve is either switched from the output of the first (adjacent) sampling zone; and the flow input to the fourth sampling zone is available from the first (input) selection valve or from the third The output switching of the (non-adjacent) sampling zone; wherein the microfluidic device preferably comprises liquid continuity substantially as shown in FIG. 10; and/or wherein the microfluidic device preferably comprises at least two flow channels, each The flow rate groove includes a plurality of flow boundaries substantially as shown in (21) of FIG. 2 or (31) of FIG. A method of exposing a plurality of liquid samples to a plurality of sampling regions, the plurality of sampling regions being contained in a microfluidic device according to any one of claims 1 to 12, the method comprising the steps of: setting at least The first (input) selection valve and the second (output) selection valve of the apparatus to provide liquid continuity from the sampling input to the sampling output via a first set of sampling zones; introducing a first liquid sample into the Sampling input for circulating and exposing the first liquid sample to the first set of sampling zones; at least setting the first (input) selection valve and the second (output) selection valve to provide via a second set of sampling zones Liquid continuity from the sample input to the sample output; and introducing a second liquid sample into the sample input for the second liquid sample to circulate and be exposed to the second set of sampling zones. The method of claim 13, wherein the sampling area is included in one of the microfluidic devices of any one of claims 8 to 12, and at least one of the setting steps further comprises setting at least one switching valve. The method of claim 13 or 14, wherein: the first set of sampling areas and the second set of sampling areas differ by at least one other sampling area, wherein the first set of sampling areas and the second set of sampling areas are preferably different All of the individual sampling areas; and/or each group of sampling areas are less than the total number of sampling areas, wherein each of the sampling areas is preferably a separate sampling area. The method of any of claims 13 to 15, further comprising repeatedly performing the setting step and the introducing step to expose the at least one additional liquid sample to at least one additional subset of sampling regions; wherein the steps are preferred The process is repeated until at least one liquid sample has been exposed to each of the plurality of sampling zones. The method of any one of claims 13 to 16, further comprising the steps of: setting at least the first (input) selection valve and the second (output) selection valve to pass through the plurality of plurality of sampling regions A sampling zone provides fluid continuity from the sampling input to the sampling output; and a common liquid sample is introduced into the sampling input for the common liquid sample to circulate and be exposed to the sampling zones of the plurality of sampling zones. The method of any one of claims 13 to 17 for detecting: a plurality of analytes in a different liquid sample; and/or one of the plurality of liquid samples. The method of claim 18, wherein: at least two of the sensing regions are each adapted to first perform the method of any one of claims 13 to 18, and then detect at least two of the common liquid samples. The presence or absence of a substance to detect the presence or absence of a different analyte; or at least two of the sampling areas are each adapted to detect the presence or absence of the same analyte, and then the method of any one of claims 13 to 18 To detect the presence or absence of the analyte in at least two liquid samples. A device comprising a microfluidic device according to any one of claims 1 to 12, wherein the microfluidic device is preferably a multi-channel biosensing device. A method of preparing a microfluidic device according to any one of claims 1 to 12, wherein the device comprises at least a secondary unit and at least one switching valve, the switching valve having any one of the preceding claims a filling/flushing function, wherein at least one of the secondary units has been previously operated, the method comprising the steps of: setting the first (input) selection valve, the second (output) selection valve, and the switching valve, Causing a liquid sample to flow through the pre-operated subunit And the second (output) selection valve does not flow into another unit of the apparatus; and a liquid sample is introduced into the apparatus to prepare the pre-operated subunit.