EP1509324B1 - Dispositif de depot localise et controle activement d au moi ns une solution biologique. - Google Patents

Dispositif de depot localise et controle activement d au moi ns une solution biologique. Download PDF

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Publication number
EP1509324B1
EP1509324B1 EP03752817A EP03752817A EP1509324B1 EP 1509324 B1 EP1509324 B1 EP 1509324B1 EP 03752817 A EP03752817 A EP 03752817A EP 03752817 A EP03752817 A EP 03752817A EP 1509324 B1 EP1509324 B1 EP 1509324B1
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EP
European Patent Office
Prior art keywords
lever
deposition
depositing
levers
reservoir
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP03752817A
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German (de)
English (en)
French (fr)
Other versions
EP1509324A1 (fr
Inventor
Christian Bergaud
Matthieu Guirardel
Pascal Belaubre
Benoit Belier
Jean-Bernard Pourciel
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Centre National de la Recherche Scientifique CNRS
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Centre National de la Recherche Scientifique CNRS
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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
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • B01L3/0244—Drop counters; Drop formers using pins
    • 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
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • B01L3/0244—Drop counters; Drop formers using pins
    • B01L3/0248—Prongs, quill pen type dispenser
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/12—Specific details about manufacturing devices
    • 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
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0433—Moving fluids with specific forces or mechanical means specific forces vibrational forces
    • B01L2400/0439—Moving fluids with specific forces or mechanical means specific forces vibrational forces ultrasonic vibrations, vibrating piezo elements
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00—Metal working
    • Y10T29/49—Method of mechanical manufacture
    • Y10T29/49995—Shaping one-piece blank by removing material
    • Y10T29/49996—Successive distinct removal operations

Definitions

  • the present invention relates to a device for depositing localized and actively controlled at least one biological solution in the form of microdrops.
  • dip-pen lithography is a technique derived from atomic force microscopy and which allows patterns to be formed on a surface using a molecular transport diffusion effect at the water meniscus formed between the tip of an atomic force microscope and the surface on which the deposit is made.
  • the operating principle is based on the difference in hydrophilic or wettability properties of the tip and the surface.
  • the surface must indeed be more hydrophilic than the tip to generate a molecular diffusion from the tip to the surface.
  • the resolution obtained may be less than one micron and it is also possible to envisage the deposition of different biological molecules, but this involves making a change of the tip (which has previously been immersed in the solution to be deposited) for each solution.
  • micro-machined silicon structures with microfabricated channels are micro-machined silicon structures with microfabricated channels, and their use is in every respect comparable to that of an inkjet system.
  • These "closed” structures, tube-shaped, are very difficult to clean, which is an obstacle to the use of the same device for depositing droplets of different liquids.
  • Patent EP0725267 discloses a micropipette electrically controlled for volumes in a range of a few hundred picoliters to a few microliters, to pipette any type of liquid specimen with or without microparticles.
  • electrospray electrospray
  • electrospray is to apply an electric field high enough to ionize and atomize the liquid to be deposited.
  • the droplets thus produced have submicron dimensions and evaporate before waiting for the deposition surface; in this way, thin films are produced.
  • the electrospray devices consist of micropipettes containing a needle-shaped electrode, so they can not be effectively washed and must be replaced each time the liquid is changed.
  • the present invention makes it possible to achieve these objectives by using, as a deposition system, one or more silicon micro-levers comprising at least one electrode making it possible to manipulate the liquid to be deposited by electrostatic effects.
  • An object of the invention is a deposition device allowing a precise and actively controlled local deposition of microdrops, in particular of diameter less than 10 microns, and more particularly of diameter of the order of 1 micron.
  • Another object of the invention is a deposition device allowing a precise and actively controlled local deposition of microdroplets on microstructures such as bridges, beams or membranes.
  • Another object of the invention is a deposition device for depositing different biological molecules.
  • Another object of the invention is a deposition device for depositing microdrops without contact with the structure or the microstructure on which the deposition takes place.
  • Another object of the invention is a deposition device for depositing microdrops by contact with a structure or a microstructure, under conditions that maintain the integrity of the structure or microstructure.
  • At least one of the above-mentioned objectives is achieved by means of a biological solution deposition device comprising at least one silicon flat lever having a central body and a tip-forming end region in which a slot or a slot is formed. groove, characterized in that it has at least one metal track formed on a face of the central body and at least partially along a said slot or groove.
  • Said slot or the groove advantageously extends from said tip to a reservoir formed in the central body.
  • said one or more metal tracks at least partially along said tank.
  • the reservoir is a non-emergent cavity formed from a main face of the central body.
  • the reservoir is constituted by a through opening formed between two opposite major faces of the central body.
  • a said slot or groove and / or a said tank and / or a said metal track is optionally coated with SiO 2 .
  • the lever advantageously has at least one hydrophobic region made of silicon or silicon oxide coated with hydrophobic silane.
  • the device has at least one implanted piezoresistance.
  • each lever has at least one integrated actuator for controlling its flexion.
  • said actuator comprises a piezoelectric layer deposited on a surface of said lever.
  • said actuator comprises a metal bimetal and a heating resistor deposited on a surface of said lever.
  • the method may be characterized in that c comprises a chemical etching or ion etching up to the buried insulating layer to define, in addition to the outline of the levers, a slot and / or an opening opening constituting a reservoir for at least one lever.
  • the method may be characterized in that c comprises a first chemical etching or ion etching of the substrate which is stopped before the buried insulating layer to define at least one groove and / or one non-emerging cavity forming a reservoir, for at least one lever and a second chemical etching or ion etching of the substrate, to the buried insulating layer to define at least the outline of the levers.
  • the first etching or ion etching can be carried out so that the outline of the levers is defined on part of their thickness.
  • a step of implanting at least one piezoresistance is provided.
  • the method also comprises a step of depositing an integrated actuator.
  • said deposition step of an integrated actuator comprises sputtering deposition of a piezoelectric film of PbZrO 3 / PbTiO 3 .
  • Said piezoelectric film is advantageously isolated from the liquid by a layer of a material chosen between: silicon oxide, PTFE called "Teflon", a polymer.
  • said deposition step of an integrated actuator comprises low pressure chemical deposition (LPCVD) of a layer of Si 3 N 4 followed by deposition by evaporation of a layer of Cr and d a layer of Au to achieve a heating resistor, thereby forming a metal bimetal.
  • LPCVD low pressure chemical deposition
  • the invention also relates to a method for sampling at least one biological solution using a device as defined above, characterized in that the sampling and the retention of said biological solution are assisted by an electric field effect by applying a difference potential between said metal tracks.
  • a measurement of the variation of the electrical resistance of said piezoresistance is carried out after sampling to determine the amount of biological solution removed.
  • the invention also relates to a method for depositing at least one biological solution using a device as defined above, characterized in that the deposition of said biological solution is assisted by an electric field effect by applying a potential difference between said metal tracks, which are maintained at the same potential, and a deposition surface having at least one conductive layer.
  • a measurement of the variation of the electrical resistance of said piezoresistance is performed after the deposition to determine the amount of deposited biological solution.
  • the invention also relates to a method of deposition of at least one biological solution using a row of devices as defined above, each comprising a piezoresistance and an integrated actuator, characterized in that the contact force of each lever with the deposition surface is determined by measuring the variation of the electrical resistance of each piezoresistor implanted and actively controlled by each integrated actuator.
  • the levers are preferably of rectangular shape (central body 1) terminated by a triangular end 2 forming a point 3.
  • a tank 6 or 7 of rectangular shape can be inserted in upper termination of the channel 4 or 5.
  • the channel may be a groove 4 formed on a portion of the thickness of the lever from a surface 11 or a through slot 5 which extends between the faces 11 and 12.
  • the channel may communicate with a non-emerging reservoir constituted by a cavity 6 formed from a main face 11 of the central body 1 of the lever, or with a through tank 7 constituted by an opening 7 formed between the main faces 11 and 12 of the central body 1.
  • FIGS. 1A and 1B illustrate the case of a slot 5, FIGS. 2A and 2B, a slot 5 and an outlet tank 7, FIGS. 3A and 3B illustrate the case of a groove 4 and FIG. a non-emerging reservoir 6, and finally FIGS. 4A and 4B illustrate the case of a slot 5 and a non-opening reservoir 6.
  • the case (not illustrated) of a lever having a groove 4 and a through tank 6 can also be implemented.
  • the metal tracks 8 and / or 9 run along the tank 6 or 7 (FIGS. 2A, 2B, 3A, 3B, 4A and 4B) and / or the groove 4 (FIGS. 3A, 3B) and / or the slot 5 (FIGS. 1B, 2A, 2B, 3A and 3B).
  • a single metal track 8 or 9 may be present.
  • an actuator constituted by a piezoelectric layer 38 (FIG. 6A) or a metal bimetallic strip comprising a layer of Si 3 N 4 33, a layer of Chrome 35 and a layer of gold 37 (FIG. 6B).
  • Both the piezoresistor 31 and the actuator 33-35-37 or 38 are isolated from the liquid by a passivation layer 32.
  • the process of manufacturing levers for the deposit is based on the techniques of collective fabrication of microelectronics. A series of technological steps is performed on a silicon on insulator substrate (SOI: silicon on insulator).
  • SOI silicon on insulator
  • the first part of the process comprises a succession of elaborations of thin layers (FIGS. 8A and 8C), and the second part consists of a series of micro-machining operations in order to define the levers.
  • the first step is a silicon oxide 22 deposition by LPCVD (low pressure chemical vapor deposition) on the front face 21 of a silicon substrate 20 having a buried oxide layer 30.
  • the oxide layer 22 serves as an insulator between the substrate and the subsequent metallizations.
  • under-stripping makes it possible to make the metal tracks 25, namely a photolithography followed by a metal deposition 25 by evaporation and then a removal of the resin. (which was used to mask the metallized regions) in acetone and with ultrasound application, and finally an annealing of the metallization.
  • the last step of the thin-film part is a second localized deposition of silicon oxide (FIG. 8C) by LPCVD to isolate the metallizations of the liquid during the use of the levers, followed by photolithography to access the contact pads. metallizations by chemical etching of the silicon oxide.
  • a front-face photolithography in the silicon layer 27 defines the contours of the levers.
  • a first plasma etching reactive ion etching or RIE
  • RIE reactive ion etching
  • the possible implantation of at least one piezoresistance can be performed before the step 8A.
  • a thin oxide is first produced before the implantation of dopants in silicon. The thickness of this oxide, the dose and the energy of the doping must be chosen to obtain a maximum sensitivity of the piezoresistance.
  • the oxide (FIG. 8A) is deposited and then opened by etching at the contacts of the piezoresistance and a metallic deposit is made (FIG. 8B) by stripping, which takes into account the tracks serving as electrodes and the tracks for the piezoresistances. The manufacturing process then continues as before.
  • One or more piezoresistors implanted on at least some of the levers make it possible to have one or more strain gauges whose variation of resistance makes it possible to detect in particular the contact of the lever with a surface. This allows in particular to ensure an adjustment of the coplanarity of the levers during a collective deposit.
  • the actuator may consist of a metal bimetal.
  • Figures 8H-8L show the different steps of making such a device.
  • a layer 33 of Si 3 N 4 is deposited by a low pressure chemical vapor deposition (LPCVD) process (FIG. 8H); then a layer 35 of chromium ( Figure 81) and a layer 37 of gold to form the heating resistor ( Figure 8L), thus forming a bimetallic strip, are deposited by thermal evaporation.
  • LPCVD low pressure chemical vapor deposition
  • Figure 81 chromium
  • Figure 8L a layer 37 of gold to form the heating resistor
  • a doped polycrystalline silicon layer can also be used as a heating resistor.
  • lithography step to define the contours of these elements, the deposition of an insulating oxide layer and realization of the electrical contacts of the heating resistor.
  • the metal tracks constitute the heart of the invention, because they make it possible to control the rise of the liquid in the slot or groove during the filling of the device, and its descent during the deposition by field effect.
  • a first technique called dielectrophoresis and proposed by Jones et al. (See document cited above), consists of using an alternating electric field to confine a polarizable liquid (water for example) in areas of strong electric field (the use of a continuous field is possible, but can induce troublesome effects, such as electrolysis of the liquid or the damage of biomolecules).
  • This field being created between two isolated electrodes and coplanar, the liquid literally "plate” on the electrodes.
  • a liquid can be "conductive" or "dielectric” depending on the frequency of the electric field applied to it.
  • the electrodes may not be coated with insulation.
  • electrowetting makes it possible to modify the wettability properties of a surface (contact angle between the surface and the liquid) by applying a potential difference between said surface and the liquid. , and thus control the effects of capillarity. If a potential difference of a few volts at 10 V is applied between the electrodes and a conductive surface, the field effect may induce a contactless deposit. A higher potential difference (beyond the kV) can induce electrospray.
  • the silicon oxide is thus used as hydrophilic compound and the monocrystalline silicon is used as hydrophobic material.
  • Such a treatment consists for example of a hydrophobic silane coupling, for example a silane having a methyl or fluorinated group as a terminus, which is deposited on silicon oxide.
  • This compound is deposited on silicon oxide in the form of self-assembled monolayers and has the advantage of being highly hydrophobic.
  • the techniques for creating residual charges in the oxide by implantation or irradiation technique are conceivable in order to increase the wettability or hydrophilicity properties of the passivation layer (coating layer). cold oxide for example).
  • the surface of the device is rendered strongly hydrophobic and the charging of the liquid is effected by the dielectrophoresis and electrowetting effects mentioned above. In this way, the cleaning of the device is facilitated and the deposition of several different liquids without contamination is made possible.
  • a three-axis micro-robot (X, Y, Z) makes it possible to use the microleviers according to the invention for the filling and depositing phases.
  • the micro-robot makes it possible to position the microstructures very precisely with respect to a surface intended to receive the deposit.
  • the deposit is then made by direct contact with the surface or by contactless field effect.
  • electrospray deposition technique electrospray
  • electrospray is also conceivable insofar as the applied field is large enough to generate nebulization and atomization of the biomolecules.
  • the robot is for example a three-axis robot X, Y, and Z available commercially, with a pitch of 50 nanometers, widely compatible with a diameter of deposits to achieve of the order of 10 to 20 microns.
  • This precision allows a fine control of the lever-deposit surface contact, thus giving a better homogeneity of the spots produced.
  • a further improvement of the contact control is obtained by the use of an actuator, for example piezoelectric or thermomechanical, integrated in the microstructure.
  • the integrated actuators can individually control the contact of each device with the surface.
  • the integrated piezoresistors make it possible to control the robot and said actuators.
  • the displacement along each axis is provided by a stepping motor.
  • Each motor powered by alternating current, is associated with a linear position sensor allowing a position control in closed loop.
  • the angle of incidence that is to say the angle of contact between the lever and the surface on which the deposit is made, has a significant influence on the size of the drops deposited. The most satisfactory results are obtained with an angle close to 60 °. It should be noted that, during the contact phase, this angle varies from 60 ° to 45 ° for a descent of the lever after contact of 50 microns (for the value of the descent distance of the lever after contact will be adopted for the following the term "depth of contact"). The greater or lesser bearing force thus varies the volume of liquid deposited.
  • the angle is made variable by a moving part fixed on the Z axis and rotated relative to the Y axis. It is possible to control this angle directly from microcontrollers connected to the control system.
  • the deposition can be carried out as follows, as illustrated by FIGS. 9A-9D.
  • the first step (FIG. 9A) consists in filling the channel and the reservoir (when it exists) machined in the axis of the levers.
  • the control software makes it possible to position the levers above the reservoir containing the liquid to be deposited and to immerse them in this liquid.
  • An electric field is then created by applying a voltage between the electrodes machined on the levers and the liquid; the levers are then moved outside the liquid and the robot positions them above the location of the first deposit to be made.
  • the volume deposited depends on the depth, the angle and the contact time.
  • the field effect can also be used to control the volume of the deposit: a decrease in the electric field between the conductive tracks increases the amount of deposited liquid, and vice versa. If a row of levers is used, the deposit is individually controlled for each lever by the integrated actuators, which act on the characteristics of the contact, and the electrodes.
  • a potential difference of some volts at 10 V is applied between the metal tracks and the deposition surface, which must be conductive, or comprise a conductive coating; the field effect (dielectrophoresis) thus induced sucks the liquid.
  • a higher potential difference can induce electrospray.

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  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Micromachines (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Steroid Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
EP03752817A 2002-05-16 2003-05-15 Dispositif de depot localise et controle activement d au moi ns une solution biologique. Expired - Lifetime EP1509324B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0206016 2002-05-16
FR0206016A FR2839662B1 (fr) 2002-05-16 2002-05-16 Dispositif de depot localise d'au moins une solution biologique
PCT/FR2003/001481 WO2003097238A1 (fr) 2002-05-16 2003-05-15 Dispositif de depot localise et controle activement d'au moins une solution biologique.

Publications (2)

Publication Number Publication Date
EP1509324A1 EP1509324A1 (fr) 2005-03-02
EP1509324B1 true EP1509324B1 (fr) 2006-07-26

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EP03752817A Expired - Lifetime EP1509324B1 (fr) 2002-05-16 2003-05-15 Dispositif de depot localise et controle activement d au moi ns une solution biologique.

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Country Link
US (2) US8079832B2 (ja)
EP (1) EP1509324B1 (ja)
JP (1) JP4243586B2 (ja)
AT (1) ATE333940T1 (ja)
AU (1) AU2003251044A1 (ja)
CA (1) CA2485749C (ja)
DE (1) DE60307095T2 (ja)
DK (1) DK1509324T3 (ja)
FR (1) FR2839662B1 (ja)
WO (1) WO2003097238A1 (ja)

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FR2862239B1 (fr) 2003-11-14 2007-11-23 Commissariat Energie Atomique Dispositif de reception d'un echantillon de fluide, et ses applications
FR2865806B1 (fr) * 2004-01-30 2007-02-02 Commissariat Energie Atomique Laboratoire sur puce comprenant un reseau micro-fluidique et un nez d'electronebulisation coplanaires
JP2007535681A (ja) * 2004-04-30 2007-12-06 バイオフォース・ナノサイエンシィズ・インコーポレーテッド 物質を表面上に堆積させるための方法と装置
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JP4712671B2 (ja) * 2006-10-31 2011-06-29 アオイ電子株式会社 ナノピンセットおよびその製造方法
KR100790903B1 (ko) * 2007-01-23 2008-01-03 삼성전자주식회사 전기전하집중과 액기둥 잘림을 이용한 액적 토출 장치 및그 방법
US8293337B2 (en) * 2008-06-23 2012-10-23 Cornell University Multiplexed electrospray deposition method
US20130062205A1 (en) * 2011-09-14 2013-03-14 Sharp Kabushiki Kaisha Active matrix device for fluid control by electro-wetting and dielectrophoresis and method of driving
US9925547B2 (en) * 2014-08-26 2018-03-27 Tsi, Incorporated Electrospray with soft X-ray neutralizer
FR3032357B1 (fr) * 2015-02-10 2017-03-10 Dev Techniques Plastiques Holding D T P Holding Inoculateur de fluide

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Publication number Publication date
US8079832B2 (en) 2011-12-20
AU2003251044A1 (en) 2003-12-02
FR2839662A1 (fr) 2003-11-21
DE60307095D1 (de) 2006-09-07
DE60307095T2 (de) 2007-02-22
CA2485749C (fr) 2011-04-12
JP2005529318A (ja) 2005-09-29
US20120111129A1 (en) 2012-05-10
WO2003097238A1 (fr) 2003-11-27
US8617406B2 (en) 2013-12-31
FR2839662B1 (fr) 2005-12-02
EP1509324A1 (fr) 2005-03-02
JP4243586B2 (ja) 2009-03-25
DK1509324T3 (da) 2006-11-27
CA2485749A1 (fr) 2003-11-27
US20060096078A1 (en) 2006-05-11
ATE333940T1 (de) 2006-08-15

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