WO2009113010A1 - Dispositif de capteur et procédé de détection de composés, de particules ou de complexes - Google Patents

Dispositif de capteur et procédé de détection de composés, de particules ou de complexes Download PDF

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Publication number
WO2009113010A1
WO2009113010A1 PCT/IB2009/050973 IB2009050973W WO2009113010A1 WO 2009113010 A1 WO2009113010 A1 WO 2009113010A1 IB 2009050973 W IB2009050973 W IB 2009050973W WO 2009113010 A1 WO2009113010 A1 WO 2009113010A1
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WIPO (PCT)
Prior art keywords
sensor device
carrier body
fluidic sample
fluidic
detection
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PCT/IB2009/050973
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English (en)
Inventor
Kasper Koch
Sander Van Berkel
Pieter Nieuwland
Floris Rutjes
Jan Van Hest
Erik Lous
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Nxp B.V.
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Application filed by Nxp B.V. filed Critical Nxp B.V.
Publication of WO2009113010A1 publication Critical patent/WO2009113010A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
    • B01F25/4331—Mixers with bended, curved, coiled, wounded mixing tubes or comprising elements for bending the flow
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/4905—Determining clotting time of blood
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877—Flow chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic

Definitions

  • the invention relates to a sensor device.
  • the invention relates to a sensor array.
  • the invention relates to a method of detecting compounds, particles or complexes in a fluidic sample, particularly using a biosensor device with small dimensions. Furthermore, the invention relates to a method of use.
  • Compounds, particles or complexes may be part of a colloidal system, which may comprise a dispersed phase and a continuous phase, that is to say a dispersion medium.
  • a colloidal system which may comprise a dispersed phase and a continuous phase, that is to say a dispersion medium.
  • blood may be described by such a system.
  • coagulation is a process by which blood forms solid clots. It is an important part of haemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a platelet-and/or fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation, fibrinolysis, platelets, other blood cells and vessel wall can lead to an increased risk of bleeding or thrombosis.
  • thrombin After initiation of coagulation several clotting factors are activated of which thrombin is the most important one. Thrombin has many effects not only in coagulation where thrombin converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions but also regulates fibrinolysis by activation of thrombin activatable fibrinolysis inhibitor, activates platelets resulting in the exposure of a procoagulant platelet surface and regulates vascular tone. The knowledge of thrombin related parameters is of importance for medical purposes.
  • the thrombogram measures both low and high reactivity of the clotting system and is sensitive to the action of all types of antithrombotic drugs, so that it can be used as a universal monitor of clotting function [H. C. Hemker, et al., Pathophysiol. Haemost. Thromb. 2003, 33, 4-15].
  • the haemostatic activity is basically dependent upon the time that thrombin is present in blood. Meaning that both the amount of thrombin that is generated as well as the length of time that it is active, play an important role. Both parameters are presented in the thrombogram depicted in Fig. 2.
  • EDP Endogenous Thrombin Potential
  • WO 2006117246 discloses a method for in vitro determining thrombin activity in a sample wherein the sample is a blood sample and thrombin generation is measured by the steps of contacting a layer of said sample containing prothrombin with a fluorogenic substrate specific for thrombin, wherein said layer has a thickness within a range of 0.05 to 5 mm and a surface within a range of 10 to 500 mm 2 , allowing thrombin to generate in said sample, measuring the fluorescence emitted from the surface of the layer, by the fluorescent group released from the thrombin-specific fluorogenic substrate as a result of enzymatic action of generated thrombin on said fluorogenic substrate.
  • a conventional biosensor may lack sufficient accuracy particularly in the presence of samples having very small volumes.
  • Using a fluorescent labeled substrate allows measuring in all kinds of media thereby approaching the in vivo system even more closely [H. C. Hemker et al, Thromb. Haemost., 2000, 83, 589-591; H.C. Hemker, et al., Pathophysiol. Haemost. Thromb., 2003, 33, 4-15]. It has also been demonstrated that measurements of thrombin generation in whole blood and under flow conditions can be performed [M. K. Ramjee, Anal. Biochem. 2000, 277, 11-18, R. F. Ismagilov et al., Analytical Chemistry, 2006, 78, 4839- 4849].
  • Microfluidic systems may have three-dimensional structures of several micrometers in diameter. An advantage of these small structures is the high surface-to-volume ratio. This limits mixing to diffusion, which result in a more specific reaction and shortened reaction time (typical mixing times for microsystems are less than one second). This gives a number of advantages such as high heat exchange efficiency, high mass transport and laminar flow.
  • reaction can be controlled and monitored better on microfluidic scale than on a larger scale such as the conventional laboratory scale.
  • Another feature is of course the smaller volume of solutions used during the reaction, which reduces the costs and environmental claims.
  • microfluidics as a new technology enables rapid diagnosis of a blood sample at the patient's bed side, the so called point-of-care-tests (POCT). It is believed that an application, which is based on a microfluidic system, can be carried out near the patient. This may facilitate a health care professional to analyze the patient's blood in a few minutes.
  • the patient can receive medical treatment in an early stage of the disease, in which the patient does not have several complications, and the progression of the disease can be monitored. Early treatment will save time and money in health care and will bring more comfort to the patient.
  • a sensor device In order to achieve the object defined above, a sensor device, a sensor array, a method of detecting compounds (for instance either with or without enzymatic activity or biological particles or biological complexes) in a fluidic sample, and a method of use according to the independent claims are provided.
  • a sensor device for instance a biosensor device, or a chemical sensor for detecting (for instance biological) compounds in a fluidic (for instance biological) sample (such as a blood or blood plasma sample, for measuring haemostatic parameters)
  • the sensor device comprising a carrier body (such as a solid body), at least two inlet units (such as wells accommodating fluids or fluidic interfaces to vials accommodating fluids) formed in and/or on the carrier body and adapted for receiving a fluidic sample and at least one reagent (for instance, one of the at least two inlet units may be adapted for receiving a fluidic biological sample and another one of the at least two inlet units may be adapted for receiving a reagent), a mixing area in fluid communication with at least two inlet units in which the fluidic sample and at least one reagent are to be mixed (for instance are brought in functional contact so as to allow any biochemical process to happen), at least two fluidic channels formed in and/or on the carrier body and
  • a method of detecting (for instance biological) compounds in a fluidic sample comprising injecting a fluidic (for instance biological) sample and at least one reagent in at least two inlet units formed in and/or on a carrier body, guiding the fluidic sample and the at least one reagent via at least two fluidic channels formed in and/or on the carrier body to a mixing area, mixing the fluidic sample and at least one reagent in the mixing area, and detecting the compounds in the fluidic sample mixed with at least one reagent.
  • a sensor array for example a biosensor array
  • a sensor array comprising a plurality of sensor devices having the above mentioned features and being formed (for instance in a matrix-like configuration, particularly in rows and columns or spiral shape) in and/or on a common carrier body.
  • a sensor device having the above mentioned features is used for measuring haemostatic parameters for a plurality of samples simultaneously in different channels. It is possible to measure one or several parameters also on one body. This is also possible by at the same time measuring (in one detection unit) separated parameters.
  • the term "sensor” may particularly denote any device, which may be used for the detection of an analyte comprising any kind of molecules, based on any kind of sensing principle such as a physical sensing principle, a chemical sensing principle or a biological sensing principle.
  • the term “biosensor” may particularly denote any device, which may be used for the detection of an analyte comprising biological molecules such as DNA, RNA, proteins, enzymes, cells, bacteria and viruses.
  • a biosensor may combine a biological liquid component (for instance reagents) with a physical substance and detector component (for instance an optical detector for sampling optical properties of a sample under analysis in the biosensor device which are modifiable by an interaction with a reagent).
  • biological compounds may particularly denote any compounds which play a significant role in biology or in biological or biochemical procedures, such as genes, DNA, RNA, proteins, enzymes, cells, bacteria, virus, phospholipid containing particles, protein-protein complexes, protein-DNA complexes etc.
  • fluid sample may particularly denote any subset of the phases of matter. Such fluids may include liquids, gases, plasmas and, to some extent, solids, as well as mixtures thereof.
  • fluidic biological samples are DNA containing fluids, blood, blood plasma, serum, mucus, saliva and interstitial fluid in subcutaneous tissue, muscle or brain tissue, urine or other body fluids.
  • a substance may comprise peptides, enzymes, proteins, polypeptides, nucleic acids, DNA strands, etc.
  • sample as used herein may refer to a biological fluid such as whole blood, plasma, for instance blood- cell-enriched plasma or cell- free plasma, serum, urine, saliva or mucus of humans or animals.
  • the sample may be obtained from healthy individuals, from individuals suspected to have or having a haemostatic disorder, from individuals with a haemostatic disorder who undergoes treatment or from individuals without haemostatic disorders who are treated with haemostatic drugs.
  • the sample can be freshly prepared or be present in frozen condition, for instance in case of the cell free samples.
  • the sample can also comprise mixtures of purified proteins of natural, synthesized or recombinant origin and/or other preparations/reagents with haemostatic activity.
  • electromagnetic radiation may particularly denote a beam of photons of any appropriate wavelength. This may include the optical spectrum (for instance the range between 400 nm and 800 nm), but may also include electromagnetic radiation of other wavelengths, like UV, infrared, microwaves, or even X-rays. According to exemplary embodiments of the invention, such electromagnetic radiation may be used for irradiating a surface of the biosensor device, which may have different electromagnetic response properties in the presence and in the absence of the biological compounds to be detected, or depending on the concentration or amount of the biological compounds to be detected.
  • reagent may particularly denote any chemical, biochemical or biological detection agent, i.e. any substance, which can be used in combination with the fluidic sample for detecting specific biological compounds included therein.
  • the biological compound is thrombin
  • at least one reagent may comprise a corresponding chromogenic substrate, fluorescence substrate or chemiluminescent substrate or any other substance (either or not coupled to and protein, peptide or antibody) required for or promoting the detection of that biological compound.
  • mixing area may particularly denote a surface portion of the carrier body, which is specifically configured or dedicated to promote or enable efficient mixing between at least two fluidic components.
  • geometrical design of a channel forming part of the mixing area may be such that a mixing force is exerted on such fluidic streams which force may be such that the different components efficiently mix with one another.
  • detection unit may particularly denote any configuration which allows to analyze the mixed components, for instance in an optical manner, to thereby derive information regarding the biological compounds under analysis.
  • the detection unit may be arranged to qualitatively or quantitatively evaluate thrombin generation in a blood sample after mixing with one or more corresponding reagents.
  • channel may particularly denote any fluidic path or fluidic conduit formed as a recess in a surface portion of the substance, formed as a for example tubular capillary within the substance, or formed on top of the substance (for instance as a strip of a material through which a fluid may be transported).
  • a method for measuring thrombin generation in a sample of a patient's blood or plasma, or in a sample containing various clotting factors is provided using a microchip containing microchannels.
  • the method may enable to measure various haemostatic parameters consuming only small amounts of sample.
  • a structure of a corresponding microchannel flow through system may be designed in such a way that mixing of the sample and the reagents rapidly occurs.
  • the design may result in an increase of the total detection area and thereby the total amount of detected units (for instance fluorescence or luminescence).
  • a method according to an exemplary embodiment of the invention may make it possible to use a set of different substrates for a simultaneous determination of different clotting factors even in one single detection area if the different chromogenic, fluorogenic or luminescent signals do not interfere. Furthermore, multiple tests may be integrated into one microchip. Automation of the whole sequence of handling may results in a robust and reliable system, which may be less error prone compared to the conventional approaches.
  • a hydrophobicity/hydrophilicity or any other relevant properties of the channels may be tuned easily by coating the channel walls, which may have a significant effect on haemostatic parameters. It is also possible to coat the channels with heparin or any other functionalization. At least one physical property of the channels may be different from the mixing area and/or detection area.
  • a thrombin generation test (TGT) system is provided performed in (micro)channels instead of a conventional wells plate geometry, thereby offering at least the same experimental information however consuming smaller quantities of plasma (for instance ⁇ 5 ⁇ l).
  • the mixing structure of the microchannel is designed in such a way that it can be used simultaneously as a detection area. Multiple substrates may be simultaneously added for the detection of various haemostatic parameters said haemostatic enzymes.
  • An integration of semiconductor components for instance a CMOS/CCD detector, light source
  • CMOS/CCD detector, light source may be feasible in flat substance design and may be easily applied.
  • a monolithically integrated microfluidic chip which allows for a spatial combination of a mixing region and a detection region, so that these two regions, which are conventionally provided separately from one another, are combined to further promote miniaturization of the device. Further, this combination may improve the time resolution of the biosensor since a result of the fluidic interaction may be detected in a time dependent manner.
  • the at least two fluidic channels may be microchannels.
  • the dimensions of the channels may be in the order of magnitude of micrometers or less.
  • the biosensor device may be adapted as a microfluidic device.
  • the volumes of the components under analysis may be in the order of magnitude of microliters or less. Substances can be guided through the biosensor device and may be, due to the miniature size of the biosensor device, used for detection on the basis of very small volumes.
  • each fluidic channel may be characterized by a depth perpendicular to a surface of the carrier body and by a width parallel to a surface of the carrier body and perpendicular to a flowing direction of the fluidic sample and the at least one reagent.
  • the depth and/or the width may have a dimension in a range between essentially 100 nm and essentially lmm, particularly in a range between essentially 1 ⁇ m and essentially 200 ⁇ m, more particularly in a range between essentially 10 ⁇ m and essentially 100 ⁇ m.
  • a length of each fluidic channel parallel to a surface of the carrier body and parallel to a flowing direction of the fluidic sample and the at least one reagent may be much larger than the width and depth, and may be in the order of magnitude of millimeters to centimeters, or more.
  • At least a part of walls of each fluidic channel may have a surface functionalization, particularly may comprise for example, a hydrophobic portion and/or a hydrophilic portion and/or other chemical or biological surface functionalization.
  • a surface functionalization particularly may comprise for example, a hydrophobic portion and/or a hydrophilic portion and/or other chemical or biological surface functionalization.
  • the mixing area may comprise a spirally shaped channel formed in the carrier body.
  • a spiral may be denoted as a plane curve trace defined by a point circling about a center but in increasing or decreasing distances from the center.
  • the spiral configuration according to the described embodiment may comprise one or several of such spirals, for example two oppositely wound spirals which are provided in an interdigitating or integrated manner.
  • the spirally shaped channel may form a common circular mixing area and detection area.
  • a planar area constituting a combined mixing and detection area having an essentially circular perimeter may be provided which allows a circular light spot to be used for excitation and optical detection.
  • Detection may be based on any phenomenon such as chromogenic, fluorescent, or chemoluminescent effects.
  • the spirally shaped channel may comprise an inlet spiral being in fluid communication with the at least two fluidic channels and being constituted by essentially concentric circular loops with essentially continuously decreasing diameter towards a center of the circular mixing area and detection area, and an outlet spiral being constituted by essentially concentric circular loops with essentially continuously increasing diameter beginning at a center of the circular mixing area and detection area, wherein the inlet spiral and the outlet spiral are coupled for fluid communication in the center of the circular mixing area and detection area (see for instance geometry of Fig. 4).
  • a fluid supplied via the inlet ports may enter the mixing and detection area at an outer circumference of its circular geometry and may approach a center thereof by being guided along fluidic loops with continuously decreasing diameter.
  • the fluid At an end of the inlet spiral, the fluid will be located close to a center of the circular mixing and detection zone. Close to this position, the fluid may enter the outlet spiral and will make circles in the opposite direction as beforehand, thereby continuously increasing the diameter of the circular loops until an outer perimeter of the mixing and detection zone is reached where the fluid may leave the circular mixing and detection zone. It has been recognized that such geometry results in a highly efficient mixing and simultaneous detection.
  • the biosensor device may comprise at least one outlet unit formed in and/or on the carrier body and may comprise at least one further fluidic channel formed in the carrier body and providing fluid communication between the mixing area and the at least one outlet unit.
  • the outlet unit may be some kind of waste container in which the fluidic mixture may be stored after analysis.
  • the carrier body may comprise any desired carrier body or substance such as a polymer body (for instance made of poly-dimethyl siloxane) or a semiconductor carrier body (for instance a silicon carrier body, a germanium carrier body, another group IV semiconductor carrier body, a group Ill-group V semiconductor carrier body such as a gallium arsenide carrier body), a glass carrier body or a plastics carrier body. At least a part of the carrier body may be optically transparent to enable an optical detection.
  • the carrier body may be made of a polymer, like or close to what is used for credit cards, bank cards, RFID- cards. This material should be bio-compatible and silicon compatible.
  • the flexible material PDMS may be appropriate, which is made on a mold. Volume and enzyme concentration constraints may have to be considered when the whole biosensor resides on a silicon-chip.
  • the detection unit may comprise an electromagnetic radiation source adapted for generating primary electromagnetic radiation (for instance a beam having a circular cross section) to be directed towards the mixing area for interaction with the mixture between the fluidic sample and the at least one reagent.
  • an electromagnetic radiation source may be a light source, for example a light emitting diode (organic and/or solid state) or a laser diode.
  • the detection unit may further comprise an electromagnetic radiation detector adapted for detecting secondary electromagnetic radiation resulting from the primary electromagnetic radiation after interaction with the mixture between the fluidic sample and the at least one reagent.
  • an electromagnetic radiation detector may be a photodiode or a CCD detector (charge coupled device) or a CMOS diode or camera. Any kind of detector being sensitive to electromagnetic radiation of a specific wavelength length may be used, for instance to enable a chromogenic, fluorescent, luminescent detection or a magnetic particle detection. A filter may be applied to select the proper wavelength.
  • the detector is capable to detect very few to even single photons (single photon counting). The detector unit and detection area are decently protected from any false light coming from the outside.
  • the biosensor device may comprise an evaluation unit adapted for evaluating detection signals (for example optical detection signals) to thereby identify or quantify the biological compounds.
  • the evaluation unit which may be a CPU (central processing unit) or a microprocessor
  • an algorithm may be stored which allows retrieving information regarding the biological compounds from the detection signal(s). For example, some mathematical processing of a measured curve may be performed, for example the first derivative of a measured spectrum may be calculated. This may allow deriving meaningful information regarding the biological compounds, for instance may allow obtaining information or parameters indicative of the thrombin generation characteristics or any other haemostatic parameter of the sample.
  • Communication from the biosensor to the outside world or vice versa can for instance be via USB-port or RFID or other electrical contacts/means.
  • the biosensor device may be adapted as a monolithically integrated biosensor chip.
  • the components of the biosensor device may be monolithically integrated in the biosensor chip to provide a miniature biosensor device which can be manufactured in a cheap manner and which can be used with a very small sample volume.
  • the biosensor device may be a hybrid device made from a polymer material containing channels for the fluids and semiconductor chips embedded or attached in or on the polymer material.
  • the biosensor device may be manufactured in CMOS technology. Any desired CMOS generation may be used, and the use of CMOS technology allows manufacturing the device with small dimensions and to use a technology, which is properly developed.
  • CMOS technology allows manufacturing the device with small dimensions and to use a technology, which is properly developed.
  • the method may comprise injecting a haemostatic factor comprising fluidic sample (for instance a whole blood sample, a blood plasma sample, or a sample having multiple haemostatic factors) in one of the at least two inlet units and injecting at least one reagent comprising a chromogenic, fluorescent, luminescent or magnetic substrate in another one of the at least two inlet units.
  • a haemostatic factor comprising fluidic sample (for instance a whole blood sample, a blood plasma sample, or a sample having multiple haemostatic factors) in one of the at least two inlet units and injecting at least one reagent comprising a chromogenic, fluorescent, luminescent or magnetic substrate in another one of the at least two inlet units.
  • the biosensor chip or microfluidic device may be or may be part of a sensor device, a sensor readout device, a lab-on-chip, an electrophoresis device, a sample transport device, a sample mix device, a sample washing device, a sample purification device, a sample amplification device, a sample extraction device or a hybridization analysis device.
  • the biosensor or microfluidic device may be implemented in any kind of life science apparatus.
  • Forming layers or components may include deposition techniques like spin coating, molding, packaging methods, CVD (chemical vapor deposition), PECVD (plasma enhanced chemical vapor deposition), ALD (atomic layer deposition), or sputtering.
  • Removing layers or components may include isotropic or anisotropic etching techniques like wet etching, plasma etching, etc., as well as patterning techniques like optical lithography, UV lithography, electron beam lithography, etc.
  • Embodiments of the invention are not bound to specific materials hence many different materials may be used.
  • conductive structures it may be possible using metallization structures, suicide structures or polysilicon structures.
  • crystalline silicon may be used.
  • silicon oxide or silicon nitride may be used.
  • Other techniques which may be implemented are polymer processing, (microinjection) molding, embossing, templating, etc.
  • the biosensor may be formed on a purely crystalline silicon wafer or on an SOI wafer (Silicon On Insulator) on a polymer card.
  • CMOS complementary metal-oxide-semiconductor
  • BIPOLAR BICMOS
  • BICMOS complementary metal-oxide-semiconductor
  • a device and a method for detecting haemostatic disorders may allow for a rapid mixing due to channel geometry resulting in fast homogenation of fluids, may allow for a lower detection limit due to a microchannel/chip spiral design, and may allow for the use of small amounts of blood plasma to perform a test.
  • haemostatic enzymes specific substrates can be used simultaneously resulting in output of multiple parameters allowing fast and efficient analysis. Multiple tests can be performed/integrated on one microchip.
  • the hydrophobicity/hydrophilicity of the channels can be tuned easily by coating the channel walls.
  • Embodiments of the present invention relate to a method for measuring thrombin generation in a sample of a patient's blood or plasma, or in a sample containing various clotting factors using a microchip containing microchannels. Furthermore, embodiments of the invention relate to a microchannel design in which the mixing area serves as the detection area.
  • chemiluminescent markers When the enzyme cuts the marker from the recognized-peptide strain, the marker may start to luminescence, without need of an excitation source. This may also apply to chromogenic and fluorogenic substrates. This is an example of a simplified embodiment.
  • the detector and a lamp unit may also be part of a USB-card reader.
  • Fig. 1 illustrates a biosensor device according to an exemplary embodiment of the invention.
  • Fig. 2 illustrates a thrombogram with its parameters showing the increase and decrease of thrombin generation in time in normal platelet poor plasma (NPPP).
  • NPPP normal platelet poor plasma
  • Fig. 3 illustrates a biosensor array according to an exemplary embodiment of the invention.
  • Fig. 4 illustrates a biosensor array according to an exemplary embodiment of the invention having multiple tests on one microchip.
  • Fig. 5 illustrates a side view of a microchip combined with a detection module according to an exemplary embodiment of the invention.
  • Fig. 6 illustrates a measured fluorescence in sample (PPP) according to procedure described in Example 1.
  • Fig. 7 illustrates a thrombogram obtained after mathematical processing of the detection signal shown in Fig. 6.
  • Fig. 8 illustrates a calibration curve, measured fluorescence according to a procedure described in Example 2.
  • Fig. 9 illustrates a schematic representation of a capillary with a detection window.
  • Fig. 10 illustrates a measured fluorescence in sample (PPP) in a hydrophilic capillary according to procedure described in Example 5.
  • Fig. 11 illustrates a thrombogram obtained after mathematical processing of the detection signal shown in Fig. 10.
  • Fig. 12 illustrates a measured fluorescence in sample (PPP) in a hydrophobic capillary according to procedure described in Example 6.
  • Fig. 13 illustrates a thrombogram obtained after mathematical processing of the detection signal shown in Fig. 12.
  • Fig. 14 illustrates a microchip design microchannel in the shape of a spiral according to an exemplary embodiment of the invention.
  • Fig. 15 illustrates a zoom of Fig. 14 in which the total detection area is highlighted.
  • Fig. 16 illustrates a mixing behavior of two different solutions in a spiral microchannel design, wherein flow speed of Rhodamine and deionized water solutions are both set at 1 ⁇ l/min.
  • Fig. 17 illustrates a micromixer according to an exemplary embodiment of the invention.
  • Fig. 18 illustrates a thrombogram measured according to procedure described in Example 10.
  • Fig. 19 illustrates a detailed view of a portion of a biosensor device according to an exemplary embodiment of the invention showing a micromixing zone.
  • a biosensor device 100 for detecting biological compounds in a fluidic sample according to an exemplary embodiment of the invention will be explained.
  • the microfluidic biosensor device 100 which is shown in a plan view in Fig. 1 comprises a carrier body 102 that is a thin cuboid solid body or substance in and/or on which various components are formed.
  • a first inlet unit 104 is adapted for receiving a fluidic sample such as a biological sample in the represented embodiment normal platelet poor plasma.
  • a second inlet unit 106 is adapted for receiving a reagent comprising, in the present embodiment, a fluorescent substrate.
  • a zigzag shaped mixing area and detection area 108 is shown, in which a zigzag-shaped channel is formed in a center of the carrier body 102 and which is in fluid communication with the two inlet units 104, 106.
  • the mixing area 108 the fluidic sample and the reagent are efficiently mixed.
  • Two micro fluidic channels 110, 112 are formed as essentially straight lines in the carrier body 102 and provide a fluidic connection between the inlet units 104, 106 on the one hand and the mixing area 108 on the other hand.
  • the carrier body 102 is a polymer substance in which the channels 110, 112, 108 are formed using an etching mask.
  • Substances injected in the inlet ports 104, 106 are transported or guided via the channels 110, 112 into the zigzag mixing zone 108.
  • the mixing of the two or more components triggers a physical, chemical or biochemical reaction or interaction.
  • a detection unit 114, 116 detect characteristics of such an interaction and may therefore derive information regarding the biological compounds. More particularly, the detection unit 114, 116 is adapted for detecting the biological compounds in the fluidic sample mixed with the reagent, wherein the detection unit 114, 116 is detecting the biological compounds at a position that equals to the mixing area 108. Therefore, due to this geometry, the mixing and the detection tasks may be performed essentially simultaneously, allowing for a compact design of the biosensor device 100, since two components are provided at one and the same position. However, the mixing area and detector area can also be physically separated.
  • the channel 110 has a depth, D, perpendicular to a surface 142 of the carrier body 102 which depth D has a dimension of 40 ⁇ m in the present embodiment. Furthermore, the fluidic channel 110 has a width, w, perpendicular to a flowing direction of the fluidic sample and the reagent, which width w has a dimension of 50 ⁇ m in the present embodiment.
  • Other channel portions of units 110, 112, 108, 120 may have similar or identical dimensions.
  • An outlet port 118 is provided, serving as a waste container in which components of the sample and the reagent may be accumulated after mixing and detection.
  • the two components are mixed in the mixing area 108 where detection is performed.
  • the mixed components are transported via an outlet fluidic channel 120 towards the waste container 118.
  • the optical detection system comprises a light source 114 for generating a primary light beam 122, which is directed towards the mixing area 108 for interaction with the mixture between the fluidic sample and the reagent.
  • the detection system comprises a photodiode 116 (which may be arranged in transmission geometry or in reflection geometry) for detecting a secondary light beam 124 resulting from the primary light beam 122 after interaction with the mixture between the fluidic sample and the reagent in the combined mixture and detection zone 108.
  • a photodiode 116 which may be arranged in transmission geometry or in reflection geometry
  • Proper wavelengths can be selected by using specific filters. In principle source and filter can also be on the same side of a card.
  • the biosensor device 100 comprises an evaluation unit 126 for evaluating the optical detection signals to thereby identify respectively for identifying or even quantifying the biological compounds.
  • the evaluation unit 126 in the present case is a CPU (central processing unit) or a microprocessor capable of controlling a) the operation of the light source 114 to which it is unidirectionally or bidirectionally coupled, b) the detector 116 to which it is unidirectionally or bidirectionally coupled, and c) an input/output unit 146 to which the evaluation unit 126 is coupled as well.
  • the input/output unit 146 is a user interface, like USB, RFID or electrical contacts via which connection is made to input elements such as a keypad, a joystick, buttons, etc.
  • output elements such as a display device, for instance an LCD device for a cathode ray tube via which results of the experiment or assay can be displayed to a user.
  • Input and output elements may be part of a (personal) computer, handheld, mobile telephone, etc.
  • the CPU 126 is coupled to a memory 148 in which an algorithm may be stored for deriving information indicative of a thrombin generation characteristic in the fluidic sample, as will be explained below in more detail.
  • the CPU 126 contains, or is connected to a temperature sensor, to collect the temperature of the biosensor during storage and use.
  • an optical based fluorescence measurement may be performed, and enzyme activity may be measured.
  • a spirally shaped detection spot may be advantageous to enlarge a fluorescent area.
  • the zigzag geometry of Fig. 1 provides for a large fluorescent area (however, alternative shapes are possible as well). Chromogenic, fluorescent, luminescent and magnetic based measurements are highly reliable and accurate. According to an exemplary embodiment of the invention, it is possible to reduce the required sample volume for enzyme activity tests in the haemostatic domain. This allows providing a biochip integrated with (flat) CMOS electronics.
  • Fig. 1 shows that the detection area 108 is also the mixing area 108. However, detection can also be performed in the outlet 120 or 118 (and/or in outlets 410, 412 shown in Fig. 3). For instance, a micro well may be constructed after the mixing area.
  • Fig. 2 shows a diagram 200 representing a thrombogram and having an x-axis 202 along which a time is plotted and an y-axis 204 along which a thrombin concentration after data processing is plotted
  • the thrombogram measures both low and high reactivity of the clotting system and is sensitive to the action of all types of antithrombotic drugs, so that it can be used as a universal monitor of clotting function [H.C. Hemker, et al, Pathophysiol. Haemost. Thromb. 2003, 33, 4-15].
  • the haemostatic activity is basically dependent upon the time that thrombin is present in blood.
  • EDP Endogenous Thrombin Potential
  • the conventional monitoring of thrombin generation may also be miniaturized resulting in a time-saving, accurate and easy-to-operate test.
  • the sample and (other) reagents can be scaled down and mixed very efficiently, resulting in a homogeneous and reliable system.
  • a method for conventional continuously monitoring of thrombin generation in platelet poor plasma (PPP), platelet rich plasma (PRP) or whole blood makes use of the fluorescent substrate Z-Gly-Gly-Arg-AMC.
  • PPP platelet poor plasma
  • PRP platelet rich plasma
  • the thrombograms are measured in a 96-well plate fluorometer equipped with a dispenser and a 390/460 nm filter set (excitation/emission).
  • Each experiment requires two sets of readings, one from a well in which thrombin generation takes place (TG well) and a second in which a calibrator is added (CL well).
  • the colour of the plasma can influence the fluorescence intensity. Therefore, each TG well needs to be compared to its own calibrator measurement.
  • experiments are carried out in quadruplicate i.e. a set of four TG wells is compared with a set of four CL wells [H.C. Hemker, et al, Pathophysiol. Haemost. Thromb.
  • Exemplary embodiments of the invention embody the determination of thrombin generation to be performed in a microchannel/microchip consuming minutes amounts of sample and reagents.
  • the results that can be obtained using the described methodology display similar behavior as conventional thrombin generation tests.
  • FIG. 3 A design of a microchip structure 400 according to an exemplary embodiment of the invention is depicted in Fig. 3.
  • This design in the present embodiment comprises a first inlet port 104, a second inlet port 106 and a third inlet port 404, channels 110, 112, 402, 120, 410, 412, the mixing/detection module 408 and waste outlets 118, 406, 407.
  • Fig. 3 shows three outlets 118, 406, 407. However, one or two outlet could be sufficient.
  • the method for continuously monitoring of thrombin generation in a microchannel/microchip in platelet poor plasma (PPP), platelet rich plasma (PRP) or whole blood makes also use of the fluorescent substrate Z-Gly-Gly-Arg-AMC. Besides this substrate, additional substrates may also be added in order to monitor the formation of multiple fluorescent markers.
  • the sample is loaded into the first inlet 104 of the microchip 400.
  • the reagent i.e. containing fluorogenic substrate and CaCl2 and activators
  • Fig. 4 depicts a microchip array 500 in which multiple tests 400 may be integrated in one microchip carrier body 102 enabling parallel detection of various haemostatic disorders.
  • Fig. 5 depicts a cross-sectional view of the micro fluidic biosensor device 400 shown in a plan view in Fig. 3.
  • Fig. 5 shows a cross-section of the spiral shaped microreactor, a micromixer that may be implemented according to exemplary embodiments of the invention may have another shape.
  • Example 1 Conventional TGT in a 96-wells plate
  • a sample (PPP) stored at -80 0 C is allowed to warm to room temperature prior to use.
  • the FIuCa solution (containing 100 ⁇ l of 1 M CaCl 2 , 25 ⁇ l of 100 mM ZGly-Gly-Arg- AMC in DMSO in 875 ⁇ l BSA 60 (pH 7.35)) and the TF/PL solution are prepared according to literature procedure (H. C. Hemker et al. Pathophysiol. Haemost. Thromb. 2003, 33, 4-15).
  • Fig. 6 illustrates a diagram 700 showing measured fluorescence in sample
  • Fig. 7 illustrates a diagram 800 showing a thrombogram obtained after mathematical processing [H. C. Hemker et al. Thromb. Haemost. 1995, 74, 134-138] of the detection signal shown in Fig. 6.
  • Example 2 Calibrator in a 96-wells plate
  • Fig. 8 illustrates diagram 900 showing calibration curve/measured fluorescence according to a procedure described in Example 2.
  • Example 3 Formation of detection window in microchannels (capillary)
  • fused silica capillaries 1000 with a polyimide coating commercially available, purchased from Poly Micro
  • a transparent detection window 1002 (typically 2-3 cm in length) is created by applying a short (typically 1- 2 seconds) external heat source.
  • the formed soot, from the coating is easily removed by a wet tissue leaving the detection window 1002.
  • This capillary 1000 is referred to a hydrophilic capillary.
  • Example 4 Preparation of hydrophobic microchannels (capillary)
  • Hydrophilic capillaries 1000 as described via the preparation in Example 3 are used to make hydrophobic channels by pumping through (approx. 100 ⁇ l, 50 ⁇ l/min) a solution of 10 ⁇ l ODS-Cl (octadecyl trichloro silane) dissolved in 1 ml toluene.
  • the solution in the capillary 1000 is left for 15-20 minutes.
  • approximately 2 ml toluene (1 ml/min) is pumped trough.
  • approximately 2 ml acetone is pumped through (1 ml/min) and the capillary 1000 is dried with pressurized dry air.
  • Example 5 TGT in hydrophilic microchannel (capillary) Hydrophilic capillaries 1000 as described in Example 3 are used for the determination of thrombin generation (TG).
  • the method for continuously monitoring of thrombin generation in a microchannel/microchip in a sample also uses the fluorescent substrate Z-Gly-Gly-Arg-AMC.
  • the sample PPP, 40 ⁇ l
  • the recorded data is analyzed according to the same procedure as for the conventional test.
  • Fig. 10 illustrates a diagram 1000 showing measured fluorescence in sample (PPP) in a hydrophilic capillary according to procedure described in Example 5 .
  • Fig. 11 illustrates a diagram 1100 showing a thrombogram obtained after mathematical processing of the detection signal shown in Fig. 10.
  • Example 6 TGT in hydrophobic microchannel (capillary) Hydrophobic capillaries 1000 as described in Example 4 are used for the determination of thrombin generation (TG).
  • the method for continuously monitoring of thrombin generation in a microchannel/microchip in a sample also uses the fluorescent substrate Z-Gly-Gly-Arg-AMC.
  • the sample PPP, 40 ⁇ l
  • the recorded data is analysed according to the same procedure as for the conventional test.
  • Fig. 12 illustrates a diagram 1200 showing a measured fluorescence in sample (PPP) in a hydrophobic capillary according to procedure described in Example 6.
  • Fig. 13 illustrates a diagram 1300 showing a thrombogram obtained after mathematical processing of the detection signal shown in Fig. 12.
  • Example 7 Design mixing area/detection area of a microchip 1500
  • microchannel structure 408 As depicted in Fig. 14 was applied. This is also beneficial for the total detection area, as the channels 408 are concentrated in a relative small area on the microchip (see Fig. 15, in which the total detection area is highlighted).
  • the microchannel structure 408 is designed using the software program CIeWIN.
  • the actual glass (Boro float®) microreactor 102 is fabricated by Micronit Micro fluidics BV (HF etched). Chip dimension: length 45 mm, width 15 mm, height 2.2 mm. Channel dimension: width 100 ⁇ m, depth 45 ⁇ m.
  • Example 8 Mixing behavior in spiral microchannel.
  • the microchip 1500 as described in Example 7 is used to demonstrate the mixing behavior of two miscible liquids.
  • a colored solution (containing rhodamine) and deionised water is used, both solutions are filtered prior to use.
  • the microchip 1500 is positioned on the microscope (Zeiss, Axiovert 40 MAT).
  • the two aqueous solutions are loaded into two syringes, which are subsequently attached via capillaries to the microchip 1500. Both solutions are pumped through the microchip 1500 with a syringe pump (New Era, NE- 1000, not shown) with a flow of 1 ⁇ l/min.
  • a syringe pump New Era, NE- 1000, not shown
  • Images 1700 are recorded with the camera (Carl Zeiss, Axiocam MRc5) mounted onto the microscope (see Fig. 16).
  • Example 9 Mixing behavior of fluids in commercial micromixer. Mixing experiments in the micromixer (Micronit Microfluidics BV (Enschede,
  • type TD 18 were performed by filling a syringe with Rhodamine B solution (1 mg/mL in deionised water) and another syringe with deionized water. Both syringes were mounted on the syringe pumps and connected to the micromixer. One pump was programmed to deliver 50 ⁇ L at a pump rate of 450 ⁇ L.min "1 . Another pump was programmed to deliver 25 ⁇ L at a pump rate of 225 ⁇ L.min "1 . The micromixer was positioned on the microscope
  • TGT in a micromixer was carried out by filling a syringe with sample (NPPP, typically 300 ⁇ L) and another syringe with reagent (typically 150 ⁇ L TF/PL solution and 150 ⁇ L FIuCa). Both syringes were mounted on the syringe pumps and connected to the microreactor. One pump was programmed to deliver 50 ⁇ L at a pump rate of 450 ⁇ L.min "1 . Another pump was programmed to deliver 25 ⁇ L at a pump rate of 225 ⁇ L.min "1 . To initiate the reaction, both pumps were started exactly at the same time, and the fluorescence in the microreactor was measured during 40 minutes by fluorescence microscopy.
  • Fig. 18 illustrates a diagram 1900 showing a thrombogram after mathematically processing [H. C. Hemker et al. Thromb. Haemost. 1995, 74, 134-138] of the detection signal.
  • Fig. 19 shows a cross-section of a channel in the micromixer 2000 (in the

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Abstract

Cette invention se rapporte à un dispositif de capteur (100) destiné à détecter des composés dans un échantillon fluidique, le dispositif de biodétecteur (100) comprenant un corps porteur (102), au moins deux unités d'entrée (104, 106) formées dans le corps porteur (102) et/ou sur celui-ci et adaptées pour recevoir un échantillon fluidique et au moins un réactif, une zone de mélange (108) en communication fluidique avec les deux unités d'entrée (104, 106) et dans laquelle l'échantillon fluidique et le ou les réactifs doivent être mélangés, au moins deux canaux fluidiques (110, 112) formés dans le corps porteur (102) et/ou sur celui-ci et fournissant une communication fluidique entre les deux unités d'entrée (104, 106) ou plus et la zone de mélange (108), et une unité de détection (114, 116) adaptée pour détecter les composés présents dans l'échantillon fluidique mélangé avec le ou les réactifs.
PCT/IB2009/050973 2008-03-13 2009-03-09 Dispositif de capteur et procédé de détection de composés, de particules ou de complexes WO2009113010A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010077784A1 (fr) * 2008-12-15 2010-07-08 Portola Pharmaceuticals, Inc. Cartouches d'essai pour des essais en flux et procédés pour leur utilisation
ITTO20100550A1 (it) * 2010-06-28 2011-12-29 Milano Politecnico Dispositivo microfluidico di mescolamento convettivo
CN102896006A (zh) * 2012-10-09 2013-01-30 中国科学院半导体研究所 微球分离筛选芯片及其制备方法
WO2013088098A2 (fr) * 2011-06-30 2013-06-20 Kalim Mir Analyse efficace d'adn ultra-long dans des canaux nanofluidiques compacts
WO2015069567A1 (fr) * 2013-11-05 2015-05-14 Arizona Board Of Regents For And On Behalf Of Arizona State University Groupement de capteurs de détection adaptative et méthode pour fournir et utiliser celui-ci
US9341639B2 (en) 2013-07-26 2016-05-17 Industrial Technology Research Institute Apparatus for microfluid detection
CN113777011A (zh) * 2017-09-14 2021-12-10 卢西拉健康公司 具有电子读出的复用生物测定装置
US12023665B2 (en) 2016-03-14 2024-07-02 Pfizer Inc. Devices and methods for modifying optical properties
US12023671B2 (en) 2016-03-14 2024-07-02 Pfizer Inc. Selectively vented biological assay devices and associated methods
US12090482B2 (en) 2016-03-14 2024-09-17 Pfizer Inc. Systems and methods for performing biological assays

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6114135A (en) * 1991-11-08 2000-09-05 Goldstein; Sheldon Multiple coagulation test system and method of using a multiple coagulation test system
US6438498B1 (en) * 2000-02-10 2002-08-20 I-Stat Corporation System, method and computer implemented process for assaying coagulation in fluid samples
US6699384B1 (en) * 1999-09-21 2004-03-02 Battelle Memorial Institute Compact electrochemical sensor system and method for field testing for metals in saliva or other fluids
US20040147032A1 (en) * 2002-12-17 2004-07-29 Martin Steven M Microsystem for determining clotting time of blood and low-cost, single-use device for use therein
US20050087122A1 (en) * 2002-05-09 2005-04-28 Ismagliov Rustem F. Device and method for pressure-driven plug transport and reaction
US20050237521A1 (en) * 2004-04-22 2005-10-27 Kowa Company, Ltd. Microchip and fluorescent particle counter with microchip
WO2007050040A1 (fr) * 2005-10-28 2007-05-03 Agency For Science, Technology And Research Unité d'immobilisation et dispositif pour l'isolement de molécules d'acides nucléiques
US20070263477A1 (en) * 2006-05-11 2007-11-15 The Texas A&M University System Method for mixing fluids in microfluidic channels

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6114135A (en) * 1991-11-08 2000-09-05 Goldstein; Sheldon Multiple coagulation test system and method of using a multiple coagulation test system
US6699384B1 (en) * 1999-09-21 2004-03-02 Battelle Memorial Institute Compact electrochemical sensor system and method for field testing for metals in saliva or other fluids
US6438498B1 (en) * 2000-02-10 2002-08-20 I-Stat Corporation System, method and computer implemented process for assaying coagulation in fluid samples
US20050087122A1 (en) * 2002-05-09 2005-04-28 Ismagliov Rustem F. Device and method for pressure-driven plug transport and reaction
US20040147032A1 (en) * 2002-12-17 2004-07-29 Martin Steven M Microsystem for determining clotting time of blood and low-cost, single-use device for use therein
US20050237521A1 (en) * 2004-04-22 2005-10-27 Kowa Company, Ltd. Microchip and fluorescent particle counter with microchip
WO2007050040A1 (fr) * 2005-10-28 2007-05-03 Agency For Science, Technology And Research Unité d'immobilisation et dispositif pour l'isolement de molécules d'acides nucléiques
US20070263477A1 (en) * 2006-05-11 2007-11-15 The Texas A&M University System Method for mixing fluids in microfluidic channels

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ISMAGILOV, R. F. ET AL.: "On-chip Titration of an Anticoagulant Argatroban and Determination of the Clotting Time within Whole Blood or Plasma Using a Plug-Based Microfluidic System", ANALYTICAL CHEMISTRY, vol. 78, no. 14, 15 July 2006 (2006-07-15), pages 4839 - 4849, XP002535377 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010077784A1 (fr) * 2008-12-15 2010-07-08 Portola Pharmaceuticals, Inc. Cartouches d'essai pour des essais en flux et procédés pour leur utilisation
ITTO20100550A1 (it) * 2010-06-28 2011-12-29 Milano Politecnico Dispositivo microfluidico di mescolamento convettivo
WO2013088098A2 (fr) * 2011-06-30 2013-06-20 Kalim Mir Analyse efficace d'adn ultra-long dans des canaux nanofluidiques compacts
WO2013088098A3 (fr) * 2011-06-30 2013-10-17 Kalim Mir Analyse efficace d'adn ultra-long dans des canaux nanofluidiques compacts
CN102896006A (zh) * 2012-10-09 2013-01-30 中国科学院半导体研究所 微球分离筛选芯片及其制备方法
CN102896006B (zh) * 2012-10-09 2015-04-08 中国科学院半导体研究所 微球分离筛选芯片及其制备方法
US9341639B2 (en) 2013-07-26 2016-05-17 Industrial Technology Research Institute Apparatus for microfluid detection
WO2015069567A1 (fr) * 2013-11-05 2015-05-14 Arizona Board Of Regents For And On Behalf Of Arizona State University Groupement de capteurs de détection adaptative et méthode pour fournir et utiliser celui-ci
US9903959B2 (en) 2013-11-05 2018-02-27 Arizona Board Of Regents On Behalf Of Arizona State University Adaptive detection sensor array and method of providing and using the same
US10180504B2 (en) 2013-11-05 2019-01-15 Arizona Board Of Regents On Behalf Of Arizona State University Adaptive detection sensor array and method of providing and using the same
US12023665B2 (en) 2016-03-14 2024-07-02 Pfizer Inc. Devices and methods for modifying optical properties
US12023671B2 (en) 2016-03-14 2024-07-02 Pfizer Inc. Selectively vented biological assay devices and associated methods
US12090482B2 (en) 2016-03-14 2024-09-17 Pfizer Inc. Systems and methods for performing biological assays
CN113777011A (zh) * 2017-09-14 2021-12-10 卢西拉健康公司 具有电子读出的复用生物测定装置

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