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WO2012127433A1 - Système microfluidique pour l'automatisation de procédures de tests pathologiques - Google Patents

Système microfluidique pour l'automatisation de procédures de tests pathologiques Download PDF

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Publication number
WO2012127433A1
WO2012127433A1 PCT/IB2012/051360 IB2012051360W WO2012127433A1 WO 2012127433 A1 WO2012127433 A1 WO 2012127433A1 IB 2012051360 W IB2012051360 W IB 2012051360W WO 2012127433 A1 WO2012127433 A1 WO 2012127433A1
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WIPO (PCT)
Prior art keywords
disc
platform
layers
fluid
layer
Prior art date
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Ceased
Application number
PCT/IB2012/051360
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English (en)
Inventor
Debapriya CHAKRABORTY
Sushant Gupta
Suman CHAKRABORTY
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Filing date
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Application filed by Individual filed Critical Individual
Publication of WO2012127433A1 publication Critical patent/WO2012127433A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/50273Containers 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 the means or forces applied to move the fluids
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16Reagents, handling or storing thereof
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0803Disc shape
    • B01L2300/0806Standardised forms, e.g. compact disc [CD] format
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0887Laminated structure
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/16Surface properties and coatings
    • B01L2300/161Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0409Moving fluids with specific forces or mechanical means specific forces centrifugal forces
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0409Moving fluids with specific forces or mechanical means specific forces centrifugal forces
    • B01L2400/0412Moving fluids with specific forces or mechanical means specific forces centrifugal forces using additionally coriolis forces
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/502707Containers 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 the manufacture of the container or its components
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/502761Containers 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 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules

Definitions

  • the subject matter disclosed herein relates to a micro fluidic system and a method for automating pathological process. More particularly relates to disc shaped microfluidic platform system and a method for automating pathological process.
  • the shortcomings of the prior art are overcome and additional advantages are provided through the provision of a system and a method as described in the description.
  • the subject matter disclosed herein solves the limitations of existing arts by providing compact and easy to use device which make use of less resources and reduces time required to conduct a test procedure.
  • a microfluidic system for automating pathological procedures.
  • the system comprises a platform (1) rotatable in predetermined direction.
  • the system further includes plurality of discs (5). These discs (5) are stacked together to form multilayered disc (5) and at least one hole is provided at centre of each disc (5).
  • the multilayer disc (5) so formed is mounted on the platform (1).
  • the system is provided with source reservoir (2) of predetermined shape formed on one of the layer of the multilayer disc (5) wherein the source reservoir (2) receives fluid sample.
  • the system includes plurality of chambers of predetermined shape which are formed on one of the layer of the multilayer disc (5), wherein said chambers are configured for retaining reagents and these chambers are connected through a micro-channel (3) formed on one of the layer of the multilayer disc (5).
  • the system is provided with destination reservoir (4) of predetermined shape which is formed on one of the layer of the multilayer disc (5), wherein said destination reservoir (4) is connectable to the source reservoir (2) through the micro-channel (3) and is configured to collect resultant fluid.
  • An optical detector is configured to detect predetermined characteristic of resultant fluid.
  • a method for performing pathological test procedures comprises placing a multilayered disc (5) on a rotatable platform (1). Once the multilayer disc (5) is placed on the platform (1), fluid samples and reagents of predetermined amount is introduced into source reservoir (2) and plurality of chambers formed on one of the layer of the multilayer disc (5) and reagents into plurality of chambers formed on one of the layers of the multilayer disc (5) . Further, upon introduction of fluid sample and reagents, the multilayered disc (5) is rotated at a predetermined speed. The rotatable disc (5) would cause mixing of fluid samples with the reagents inside a microfluidic channel. Once, the operation of mixing is completed, a resultant fluid is obtained as a result of the mixing operation and is stored in destination reservoir. Now, characteristics of the resultant fluid are determined using the optical detector to complete the pathological test procedure.
  • a method of manufacturing a microfluidic system for automating pathological test procedures comprises machining patterns (6) on polycarbonate (P) disc (5) and adhesive layers (A). At least one hole is made at centre and periphery of each of the layer. Once this is done, all the layers are staked together to form a multilayer disc (5) by aligning the hole (7) formed at the periphery of each layer; and later the disc (5) is mounted on a platform (1).
  • Figure 1 shows interplay of forces on the outlined microfluidic platform (1) and shows a disc (5) rotating with angular velocity ⁇ .
  • FS T , F D , F R , FC in the figure represent surface tension, viscous drag, centrifugal force and coriolis force.
  • Figure 2 shows isometric and side views of the microfluidic platform (1) and also illustrates mounting of the disc (5) on a drive motor.
  • FIG 3 shows Layers P, A, P, A, P from left to right (P: Polycarbonate layer, A: adhesive layer). All of these are stacked together to give a rotating disc (5). Patterns (6) and reservoirs are designed on the three internal discs (5) to obtain predetermined fluid motion.
  • Figure 4 illustrates manual washing procedure for a typical test like Widal. Each circle represents a test tube. Reagents are diluted serially till a desired concentration is reached.
  • Figure 5 shows a portion of the disc (5) showing the washing procedure using the system.
  • reagents get transferred automatically (by interplay of forces on a rotating platform (1)) from the source reservoir (2) near the centre to the destination reservoir (4) near the rim of the disc (5).
  • Figure 6 shows a portion of the disc (5) showing an integrated series of mixing operation taking place in the system.
  • Figures 7 and 8 illustrate the configuration of disc (5) showing the micro-channel (3) along with the direction of the motion of the disc (5) and fluid sample.
  • Figure 9 illustrates the photographic image of the configuration of disc (5) showing the micro-channel (3).
  • the subject matter disclosed herein relates to a microfluidic system and a method for automating pathological process.
  • the present disclosure provides an aid for faster pathological detection with reduced cost by minimising human interventions and reduction in usage of chemicals and other ingredients by integrating liquid interfacing and detection units as well as means for quality control.
  • a patient's samples for an example, urine, blood, sputum, etc. can be inserted through designated incisions into the system developed. Then this is transported and manipulated in a rapid, efficient and controlled manner to the designated reservoir. This replaces the conventional technique of conducting pathological tests using bulky retorts, tubes, flasks etc.
  • the disclosure provides the device which is capable of carrying a multiple tests in every cycle apart from catering to a large number (70%) of diagnostic tests.
  • the disc (5) containing microfluidic channels are fabricated by using a lamination technique by stacking polycarbonate discs (5) using pressure sensitive adhesive film layers. Various diameters of milling bits and drill bits are utilized for the computer numerical control (CNC) micromachining. This can also be achieved using laser.
  • the CNC-machined disc (5) system consists of three polycarbonate discs (5) and two pressure sensitive adhesive layers. The three polycarbonate discs (5) constitute the top plate, the middle plate and the bottom plate of the five layer disc (5) assembly. Each of these polycarbonate discs are bonded by pressure sensitive adhesive layers in which micro-channel (3) is cut by a vinyl cutter or computer plotter or laser.
  • the apparatus or platform (1) of the present disclosure helps in reducing the use of consumables required for pathological detection, such a platform (1) can substitute the standard consumables like glass slides, centrifuge tubes and microwell plates.
  • Disc (5) based platform (1) is efficient in integrating different steps in a non-intrusive manner.
  • a variety of operations including valving, separation, mixing, heating and optical detection can be carried out in the integrated platform (1).
  • the device is very suitable for use in pathological laboratories and rural healthcare centers as it requires unskilled to semi-skilled labor for operation. Apart from minimizing the human intervention and improving efficiency, it decreases the costs by up to 40%.
  • the platform (1) of the present disclosure is helpful in eliminating centrifuge as it essentially uses centrifugal force to drive the flow.
  • Different fluidic operations like mixing, valving, separation can be easily integrated under single platform (1).
  • Multiplexing different operations can be easily performed in a disc (5), which implies a single disc (5) may be used to perform several tests from a single blood sample.
  • this platform (1) does not require much human intervention, it can be easily used to cater to the needs of the rural India, where skilled labour and sophisticated instruments are not available.
  • the pathological test procedures, being automated will be more reliable and effective. The chemicals used will be drastically less as compared to the current techniques and will result in enormous reduction in the costs of the test.
  • Fig. 1 illustrates interplay of pathway thickness and rotation speed to realise the motion of fluid from one chamber to another.
  • Centrifuge is inherently built in by virtue of the nature of the platform (1). All these can be attributed as interplay of four distinct forces on a rotating platform (1) namely, coriolis force, centrifugal force, viscous drag and surface tension. These forces in turn are controlled by two factors: rotational speed and design of the incisions and reservoirs on the disc (5).
  • Fig. 2 illustrates an apparatus that exploits micro fluidic platform (1) to automate diagnostic tests.
  • the disclosure provides a diagnostic tool that exploits a combination of centrifugal, coriolis, viscous drag and surface tension forces to manipulate chemical reagents and patient samples and to carry out pathological procedures in an automated fashion.
  • the platform (1) consists of a five layered two-sided polycarbonate disc (5).
  • a single disc (5) is shown in the figure. 9.
  • the disc (5) is made up of acrylic or polycarbonate (P) and two-sided Flex Mount adhesive layer (A). These layers are designed and stacked together in five layers viz. P, A, P, A, P in the order of occurrence.
  • the P and A layers consist of several user-defined patterns (6) to enable deliver the fluids from one chamber to another. These patterns (6) can support multiple diagnostic tests on a single disc (5) that provide to the same or different symptom.
  • the structure further includes the drive that consists of an optical detector and an encoder motor.
  • the motor is controlled by AVR 40 Pin Rapid Robot Controller Board (ATMega32) using Pulse Width Modulation (PWM) or Proportional- Integral-Derivative (PID) controller.
  • PWM Pulse Width Modulation
  • PID Proportional- Integral-Derivative
  • the micro fludic platform is rotated in a predetermined speed. The speed in which the micro fludic platform operates ranges from 5rpm to 3000rpm.
  • Each diagnostic test has a distinct series of programmed steps that execute when a particular test is chosen from the bundled computer software or an option in the motor hardware itself.
  • An optical detector (colorimetric analyser or a high speed camera) can move along a radius of the disc (5) and gather visual information about the reagents within the disc (5).
  • Figures 4, 5 and 6 of the disclosure illustrate the microfluidic operations.
  • Several different fluid operations that are required in a pathological test can be integrated in a series or parallel fashion on the aforementioned disc (5). These operations include but are not limited to mixing, separation, valving, centrifuging, heating and optical detection.
  • Mixing involves fluids in two or more reagent chambers which come together in a common pathway leading to a destination reservoir (4), mix together while flowing and get collected in the target reservoir.
  • manual washing procedures for a typical test like Widal is illustrated in figure 4.
  • each circle represents a test tube.
  • Reagents are diluted serially as shown till a desired concentration is reached.
  • reagents get transferred automatically (by interplay of forces on a rotating platform (1)) from the reservoirs near the centre to the reservoirs near the rim.
  • Fig. 7 illustrates the view of microchannel connecting the source and destination reservoir (4).
  • the disclosure provides a microfluidic system for controlled generation and manipulation of microbubble. Bubbles of micrometer length scales have scientific and technological implication, primarily to emerging applications in the fields of food processing, targeted drug delivery, ultrasound imaging, heavy metal removal during mineral processing, development of bubble based logic circuits, and controlled release of chemicals. The present disclosure additionally exploits the effects of the forces due to angular acceleration as well, for tuning the flow features. Frequency and dimensions of the bubbles generated may be explicitly controlled by designed variations of the rotational speeds for a given combination of fluids and dimensions of the pertinent fluidic pathways.
  • Fig. 8 illustrates the system in analysing anomalous mixing behaviour.
  • the characteristics of two-fluid mixed in T-shaped microchannel is analysed using a rotating platform (1).
  • Three regimes of mixing were identified based on the distinct flow behaviour.
  • a diffusion based mixing regime was obtained for low rotation speeds.
  • a coriolis force based mixing regime was observed for intermediate rotation speeds.
  • flow instability based mixing regime was observed.
  • Some techniques utilize mechanical pulsation of the fluids to create change in the flow pattern, wherein chaotic flows are induced to the flow. Specific geometries of microchannel are used to obtain different flow rates and different combination of samples.
  • the present disclosure provides the CD based platform which can perform efficiently for wide variety of samples. Also, wide range of flow rates can be obtained just by varying the rpm of the motor and many identical operations can be easily implemented.
  • the polymeric materials used in micro fludic platform (1) are amenable to mass production.
  • the disclosure provides an improved qualitative and quantitative insight regarding interplay of the related physical parameters governing the centrifugal capillarity, including a dynamical evolution of the contact line motion, by employing a simplistic approach that compares well with both rigorous full-scale numerical predictions as well as with the experimental findings.
  • Centrifugal force is the primary driving force for the capillary front with surface tension effects aiding it, resisted by the opposing viscous forces.
  • the capillary is hydrophobic, the surface tension opposes the motion of the liquid front.
  • the capillary is made hydrophilic and hence surface tension aids the motion.
  • microfluidic platform (1) of the present disclosure The manufacturing procedure of microfluidic platform (1) of the present disclosure is explained in detail herein. Firstly, a design of each layer of the disc (5) is worked out in AutoCAD/Solidworks. The design of each layer is then aligned and matched to get a fitting. Further, table-top CNC or laser is used to realise the patterns (6) on P layers. A vinyl cutter or laser is used to do the same for T layers. Apart from the central hole (to make it a disc (5), a small hole (7) is made near the periphery of each of the layers to restrict the degree of motion of these layers and to ensure proper alignment.
  • the method of detection includes the procedure of inserting the fluid through the inlet, so that it does not fill the capillary with the aid of surface tension only.
  • a high speed camera was used to capture the images for different stroboscopic sequences (only for the laboratory purpose experiments). When the same position of the disc (5) passed under the camera, the strobe was triggered. Since the disc (5) spun at the same rate at which the strobe light was triggered, a fixed position of the disc (5) was highlighted in each turn. The images of the partially filled capillaries could be captured via the camera and were subsequently transferred to a computer for data storage.
  • the platform (1) disclosed in the present disclosure saves chemicals used in the test.
  • the platform (1) saves 83.33% of chemicals required or carrying out test procedure and thus saving the cost
  • the platform (1) of the present disclosure is completely automated. Therefore, no expenditure on personnel for doing the above mentioned steps and thus saving considerable amount of time.
  • the disclosure helps in reducing cost for conducting a test by about 38%o to existing test procedure.
  • microfludic platforms discussed herein can be used for various operations and few of them have been listed herein which are capillary test strips, lateral flow assays, "the microfludic large scale integration" approach, centrifugal microfludics, the electrokinetic platform, pressure driven droplet based microfludics, electrowetting based microfludics, SAW driven microfludics and "free scalable non-contact dispensing". Also, the present disclosure can be used to study the fluid dynamic characteristics of a fluid for eg. The capillary filling dynamics in centrifugally actuated microfludic platforms with dynamically evolving contact line motion for wetting fluids, etc. Hence, a person skilled in art can infer that the microfludic platform can be utilized for conducting various operations. Equivalents

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

La présente invention concerne un système microfluidique conçu pour automatiser les procédures pathologiques. Il comprend une plateforme (1) capable de rotation dans un sens prédéterminé. Le système comprend une pluralité de disques (5). Ces disques (5) sont empilés les uns sur les autres de façon à former un disque multicouche (5), au moins un trou étant ménagé au centre de chaque disque (5). Le disque multicouche (5) ainsi constitué est monté sur la plateforme (1). Le système est également pourvu d'un réservoir source (2) et d'un réservoir de destination (4) sur l'une des couches du disque multicouche (5) qui retient respectivement le fluide échantillon et le fluide résultant, ces réservoirs étant reliés entre eux au moyen d'un micro-canal (3). Le système comprend en outre une pluralité de chambres qui sont formées sur l'une des couches du disque multicouche (5), ces chambres étant configurées de façon à retenir les réactifs. D'autres réactifs provenant des ces chambres sont amenés à l'échantillon fluide au moyen du micro-canal (3). L'invention comprend également un détecteur optique configuré pour détecter une caractéristique prédéterminée du fluide résultant.
PCT/IB2012/051360 2011-03-24 2012-03-22 Système microfluidique pour l'automatisation de procédures de tests pathologiques Ceased WO2012127433A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1077/KOL/2010 2011-03-24
IN1077KO2010 2011-03-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10542922B2 (en) 2013-03-26 2020-01-28 The Trustees Of Columbia University In The City Of New York Fluid extraction and drug delivery system and methods using microneedles
WO2021218537A1 (fr) * 2019-11-22 2021-11-04 京东方科技集团股份有限公司 Puce et système de détection

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US20020137218A1 (en) * 1995-12-18 2002-09-26 Alec Mian Devices and methods for using centripetal acceleration to drive fluid movement in a microfluidics system
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WO1998007019A1 (fr) * 1996-08-12 1998-02-19 Gamera Bioscience Corporation Microvalve capillaire
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MAXIMILIAN FOCKE ET AL: "Lab-on-a-Foil: microfluidics on thin and flexible films", LAB ON A CHIP, vol. 10, no. 11, 1 January 2010 (2010-01-01), pages 1365, XP055024289, ISSN: 1473-0197, DOI: 10.1039/c001195a *
MAXIMILIAN FOCKE ET AL: "Microstructuring of polymer films for sensitive genotyping by real-time PCR on a centrifugal microfluidic platform", LAB ON A CHIP, vol. 10, no. 19, 1 January 2010 (2010-01-01), pages 2519, XP055032260, ISSN: 1473-0197, DOI: 10.1039/c004954a *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10542922B2 (en) 2013-03-26 2020-01-28 The Trustees Of Columbia University In The City Of New York Fluid extraction and drug delivery system and methods using microneedles
WO2021218537A1 (fr) * 2019-11-22 2021-11-04 京东方科技集团股份有限公司 Puce et système de détection

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