EP1492724A1 - Dispositifs microfluidiques dotes de nouvelles surfaces internes - Google Patents

Dispositifs microfluidiques dotes de nouvelles surfaces internes

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Publication number
EP1492724A1
EP1492724A1 EP03710598A EP03710598A EP1492724A1 EP 1492724 A1 EP1492724 A1 EP 1492724A1 EP 03710598 A EP03710598 A EP 03710598A EP 03710598 A EP03710598 A EP 03710598A EP 1492724 A1 EP1492724 A1 EP 1492724A1
Authority
EP
European Patent Office
Prior art keywords
coat
wettable
substrates
microchannel structures
microfluidic device
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.)
Withdrawn
Application number
EP03710598A
Other languages
German (de)
English (en)
Inventor
Helene Derand
Frida JERNSTRÖM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gyros Patent AB
Original Assignee
Gyros AB
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from SE0201086A external-priority patent/SE0201086D0/xx
Application filed by Gyros AB filed Critical Gyros AB
Publication of EP1492724A1 publication Critical patent/EP1492724A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
    • C23C16/22—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the deposition of inorganic material, other than metallic material
    • C23C16/30—Deposition of compounds, mixtures or solid solutions, e.g. borides, carbides, nitrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00783—Laminate assemblies, i.e. the reactor comprising a stack of plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00837—Materials of construction comprising coatings other than catalytically active coatings
    • 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

Definitions

  • the present invention concerns a microfluidic device that has inner surfaces with chemical surface characteristics that have been introduced in a new way.
  • a microfluidic device typically comprises one, two or more microchannel structures, which are defined between two essentially planar and parallel substrates that are apposed to each other.
  • the two substrate surfaces that define the microchannel structures comprise microstructures in the form of grooves and/or projections such that the microchannel structures can be formed when the two surfaces are apposed.
  • each microchannel structure is defined between the surfaces of two or more planar substrates that are layered on top of each other. If different sections of a microchannel structure are defined between different pairs of planar substrates, there typically are holes in the substrates so that the sections are in communication with each other. Either one or both of the surfaces that are to define a section of a microchannel structure comprises microstructures such that the desired section of a microchannel structure will be formed when the surfaces are joined together.
  • Separate microchannel structures may be defined between additional essentially planar substrates.
  • the device is microfluidic in the sense that one or more liquid aliquots can be transported between different functional parts of the individual microchannel structures in order to process the aliquots.
  • the purpose of the transport is to carry out predetermined process protocols, for instance for assaying one or more constituents of a sample aliquot or to synthesize an organic or an inorganic compound.
  • the liquid aliquots are typically aqueous, i.e. based on water and mixtures between water and water-miscible organic solvents.
  • non-specific adsorption and “fouling” mean undesired adsorption of compounds to inner walls of the microchannel structures.
  • the term also includes inactivation of bioactive compounds by the walls, for instance denaturation of proteins.
  • the compounds are present in the liquid used and are primarily reagents.
  • the reagents may be proteins and/or other biopolymers and/or other bioorganic and synthetic organic compounds. Analytes are included in the term "reagent”. 5
  • One common method is to subject a substrate surface, for instance made in plastics, to various forms of plasma treatment (Chan et al., Surface Science Reports 24 (1996) 1-54; and Garbassi et al, Polymer Surfaces - From Physics to Technology, John Wiley (1998)
  • a plasma reactor which is a vacuum vessel containing a gas at low pressure (typically 10 to 1000 mTorr).
  • a plasma also called glow discharge
  • reactive species like ions, free radicals and vacuum-UN photons. These species may react with other species and/or with the surface and cause a chemical modification of the 0 substrate surface with properties depending on the nature of the gas and on the plasma parameters.
  • Gases like oxygen and argon are typically used for hydrophilisation and/or adhesion improvement on plastics, while vapors of organic precursor compounds can be used to apply thin coatings for a number of different purposes (Yasuda, Plasma Polymerization, Academic Press 1985). 5
  • vapours of organic precursor compounds have been used to produce surfaces that are wettable by aqueous liquids but the hydrophilicity has been moderate and not utilized to facilitate transport of aqueous liquids in microchannels.
  • the primary goal has been to introduce coats that have a low non-specific adsorption, for
  • WO 9958245 (Larsson et al) and WO 9721090 (Mian et al) are examples of publications that in general terms suggest microfluidic devices in which the inner surfaces of the microchannel structures have been made hydrophilic by gas plasma treatment, coating of hydrophobic surfaces with hydrophilic polymer etc.
  • a first object of the invention is to present a surface modification method that meets this desire.
  • This object also includes a microfluidic device of the kind just mentioned wherein at least a part of the inner surface of its microchannel structures has been modified by this kind of method.
  • One important problem with respect to microfluidic devices is to obtain surfaces with a sufficient hydrophilicity to supportliquid transport through a microchannel structure combined with a sufficiently low non-specific adsorption (anti-fouling) of reagents in order to accomplish reliable and reproducible results.
  • the severity of the fouling problem increases with the surface to volume ratio, i.e. it increases when a cross sectional dimension decreases, for instance from ⁇ 1000 ⁇ m to ⁇ 100 ⁇ m to 10 ⁇ m and/or from ⁇ 1000 ⁇ l to ⁇ 100 ⁇ l to ⁇ 10 ⁇ l to ⁇ 1 ⁇ l to ⁇ 100 nl to ⁇ 50 nl.
  • a second object of the invention is to provide new surface modifications that have a sufficient wettability combined with a sufficiently low non-specific adsorption for a reliable and reproducible mass transport and processing of reagents by a liquid flow through a microchannel structure. This object thus aims at optimizing wettability and anti-fouling in relation to each other.
  • a third object is directed to a microchannel structure that is present in a microfluidic device and comprises two or more different functional parts, at least one of which comprises inner surfaces of a sufficient hydrophilicity for a liquid aliquot to penetrate completely the functional part by capillary force once having wetted the entrance of the part. The demand for a sufficiently low non-specific adsorption remains.
  • the present inventors have recognized that the above-mentioned objects can be achieved by treating the channel surfaces with gas plasma, which comprises one or more organic precursor compounds in gas form.
  • gas plasma which comprises one or more organic precursor compounds in gas form.
  • the obtained surface characteristics (for instance hydrophhihcity or hydrophobicity) is determined by the selection of the organic precursor compound and/or the process parameters applied to create the gas plasma as outlined below.
  • the first aspect of the invention is a method for the manufacture of a microfluidic device of the kind described above in order to introduce a predetermined degree of wettability (hydrophilicity and/or hydrophobicity) on an inner surface of said microchannel structures.
  • the method is characterized in comprising the steps of: (i) providing two essentially planar substrates (I and II) of the type described under the heading "Technical Field", (ii) placing either one or both of the substrates in a gas plasma reactor, and creating within said plasma reactor a gas plasma containing an organic precursor compound, said organic precursor compound and the conditions in the reactor being selected such that a coat of the predetermined degree of wettability is formed on a selected part of the surface of the substrate/substrates, (iii) removing the substrate/substrates from the plasma reactor (iv) adhering the surface of substrate I to the surface of substrate II so that at least an enclosed section of each of microchannel structures are formed between the two surfaces, (v) optionally joining further planar substrates to complete the microchannel structures.
  • complete enclosed microchannel structures are defined between substrate I and II, i.e. the section referred to under the heading "Technical Field” corresponds to a complete microchannel structure, except for various ports that may be present as holes in the substrate
  • additional steps may involve (a) a gas plasma treatment utilizing the same or another precursor compound and/or the same or other conditions, and/or (b) some other coating procedure.
  • alternative (a) may be carried out without removing and re-inserting the substrate/substrates from/into the gas plasma reactor.
  • step (ii) If only a part of a substrate surface is to be coated in step (ii) or in any of the additional steps, appropriate masking and/or unmasking may be done before or after such acoating step (including sequence of steps). Parts that are masked/unmasked maybe present in either one or both of the substrate surfaces, for instance on a part comprising microstructures. Washing steps may be included between steps if appropriate.
  • Microstructured areas that are not going to be coated in this step are typically masked.
  • the precursor compound and the plasma conditions for the gas plasma are selected as outlined below.
  • the uncoated areas thus exposed may be further processed, for instance to render them non-wettable (hydrophobic) in order to create passive (non-closing) valves and/or anti-wicking means and/or inlet or outlet vents to ambient atmosphere.
  • step (ii) is to introduce a coat that is non-wettable (hydrophobic coat) on selected parts of the microstructures. Areas on which other surface characteristics are desired are then typically masked.
  • the non-wettable coat may be introduced for creating local surface breaks of the same type as indicated in the preceding paragraph.
  • the remaining parts may be intended for liquid transport and therefore typically need to be processed to surfaces that are wettable by inserting steps according to either alternative (a) or alternative (b) above after step (ii). Remasking for these additional steps is often advantageous for similar reasons as for the first variant.
  • the uncoated area after unmasking inherently comprises a desired wettability (either by being wettable or non- wettable), there is no need to introduce any additional surface treatment steps before step (iv).
  • a third variant of step (ii) is to introduce a coat that is sufficiently wettable or sufficiently non-wettable, but not with sufficiently low non-specific adsorption (anti-fouling), or vice versa.
  • an additional step according to alternative (a) or (b) may be used to modify the coat to exhibit the missing characteristics while at the same time retaining an essential part of the surface characteristics created in step (ii).
  • the same masking can be utilized for the two coating steps. Demasking and remasking between step (ii) and an additional step may then not be required.
  • the term “wettable” means that a surface have a water contact angle that is ⁇ 90° (hydrophilic surface).
  • non-wettable refers to a surface that have a water contact angle > 90° (hydrophobic surface).
  • the liquid contact angle in the individual parts should primarily be wettable, preferably with a water contact angle ⁇ 60° such as ⁇ 50° or ⁇ 40° or ⁇ 30° or ⁇ 20°.
  • Local surface breaks that are to be used for valving and/or anti-wicking, for instance, are important exceptions from this general rule.
  • Local surface breaks are typically non- wettable with water contact angles > 90°, such as > 100° or > 110° or > 120°.
  • difference in wettability (in water contact angles) between a local surface break and a bordering surface are > 50°, such as > 60° or > 70°. All figures refer to values obtained at the temperature of use, typically 25 °C, and with water as the liquid.
  • Microchannels are typically defined by a limited number of well-defined walls, for instance a bottom wall, a top wall and two sidewalls. These walls may derive from different substrates. Locally at least the walls derived from the same substrate are wettable/non-wettable to the same extent. In the case the surface characteristics of a channel is intended to facilitate liquid transport and the walls derived from one of the substrates is non-wettable this can be compensated if the wall(s) derived from the other substrate is(are) sufficiently wettable (i.e. has/have a sufficiently low water contact angle). The substrates.
  • Each of the two planar substrates may comprise microstructures in the form of projections and/grooves as discussed above.
  • only one of the two substrates comprises microstructures that then are in the form of open microchannel structures or open sections of the microchannel structures.
  • the other substrate is used to cover these open structures.
  • Either one or both of the substrates may have through-going holes that are associated with individual microchannel structures. These holes may be used as inlets or outlets for liquids and/or as inlet or outlet vents for air. In the case different sections of a microchannel structure are defined between different pairs of substrates this kind of holes may provide communication between the different sections.
  • the substrates may be made from inorganic or organic material.
  • Typical inorganic materials are silicon, quartz, glass etc.
  • Typical organic materials are polymer materials, for instance plastics including elastomers, such as silicone rubber (for instance poly dimethyl siloxane) etc.
  • Polymer material as well as plastics comprises polymers obtained by condensation polymerisation, polymerisation of unsaturated organic compounds and/or other polymerisation reactions.
  • the microstructures may be created by various techniques such as etching, laser ablation, lithography, replication by embossing, moulding, casting etc, etc. Each substrate material typically has its preferred techniques.
  • plastics From the manufacturing point of view, substrates exposing surfaces and microstructures in plastics are many times preferred because the costs for plastics are normally low and mass production can easily be done, for instance by replication. Typical manufacturing processes involving replication are embossing, moulding, casting etc. See for instance WO 9116966 (Pharmacia Biotech AB, Oh an & Ekstrom).
  • the preferred plastics was polycarbonates and polyolefms based on polymerisable monomeric olefins that comprise straight, branched and/or cyclic non- aromatic structures. Typical examples are ZeonexTM and ZeonorTM from Nippon Zeon, Japan.
  • Suitable polymers may be copolymers comprising different monomers, for instance with at least one of the monomers discussed above.
  • Plasma variables and the gas plasma reactor typically has a frequency in the radiowave or microwave region, i.e. kHz-MHz or GHz respectively.
  • the modification on the polymer surface caused by the plasma will depend mainly on a number of internal plasma parameters such as: type of species present in the plasma, spatial distributions, energy distributions and directional distributions.
  • the species typically derives from one or more organic precursor compounds. In turn these parameters depend in a complex way on the external plasma parameters: reactor geometry, type of excitation, applied power, type of process gas, gas pressure and gas flow rate.
  • results of a treatment may depend on the design of the reactor vessel used meaning that the optimal interval to a certain degree will vary from one reactor design to another.
  • the results may also depend on where in the reactor the surface is placed during the treatment.
  • a suitable reactor vessel should enable electric excitation power input for instance in the microwave or radio wave ranges.
  • the required intensity of the plasma will depend on the variables discussed above. Satisfactory gas plasmas may be found in the case the electric excitation power applied is ⁇ 300 W, with preference for ⁇ 100 W.
  • the pressures are typically ⁇ 200 mTorr, with preference for ⁇ 100 mTorr.
  • the design of the reactor vessel should enable introduction of the vapour phase of the organic precursor into the reactor chamber. This includesthe option of heating of the reactor chamber and/or flask containing the organic precursor.
  • the reactor vessel should be designed to facilitate homogenous plasma distribution in the reactor chamber. More details on parameters influencing plasma polymerisation can be found in h agaki, N., "Plasma surface modification and plasma polymerisation.” Technomic Publisching company, Inc., USA, 1996.
  • the chemical structure of the a coat such as degree and type of cross-linking, swelling, kinds of functional groups exposed to a surrounding liquid, etc determines the chemical surface characteristics, primarily wetting/non-wetting ability including hydrophilicity and hydrophobicity, and non-specific adsorption of various compounds such as proteins and/or other biopolymers and bioorganic compounds.
  • XPS X- ray photoelectron microscopy
  • static SIMS static secondary ion mass spectrometry
  • liquid contact angle methods atomic force microscopy
  • AFM atomic force microscopy
  • NEXAFS near edge X-ray adsorption fine structure
  • FTIR FTIR
  • chemical derivatization See Johnston et al (J. Electron Spectroscopy and Related Phenomena 81 (1996) 303-317).
  • a sufficiently hydrophilic coat exposes neutral hydrophilic groups to a liquid in contact with the coat, in particular lower alkyl ether, such as ethylene oxy, hydroxy groups etc, and is essentially free of aromatic structures.
  • the coat should also be essentially free of charged or chargeable groups, in particular if a low non-specific adsorption is required.
  • Chargeable groups are karboxy (-COOH), amino (-NH ), etc).
  • Non-chargeable groups are hydroxy bound to sp 3 -hybridized carbon, ether, amido etc.
  • fragmentation of the precursor compound depends on W/FM where W is the RF power applied, and F and M are the flow rate and the molecular weight, respectively, of the organic precursor compound.
  • Other variables that have been studied are: (a) the effect of pulsed radiofrequency (RF) discharges on fragmentation of the precursor compound in relation to an increase of the presence of precursor structures in the deposited coat, (b) the location of the substrate in the gas plasma reactor with the idea that a location adjacent but not submersed in the plasma will increase the degree of precursor structures in the coat etc.
  • An increase in precursor structures in a deposited coat has also been suggested if there is a negative temperature gradient between the plasma and the substrate to be surface modified. See Ohkubo et al (J. Appl. Polym.
  • the organic precursor compound typically is polymerisable by which is meant that the compound is capable of forming a high molecular weight insoluble aggregate on the surface of the substrate. This may involve traditional polymerization reactions or take place by degradation, rearrangement and extensive reactions of the precursor compound and/or of the intermediary species formed in the gas plasma.
  • an organic precursor compound In order for an organic precursor compound to function in the present invention it must have a sufficiently high vapour pressure at the selected temperature within the plasma reactor. This also means that precursor compounds that have a low tendency for hydrogen bonding may have advantages compared to precursor compounds of the same size that have a strong tendency for hydrogen bonding.
  • Small precursor compounds may also have advantages, e.g. with molecular weights ⁇ 2000 dalton, such as ⁇ 1000 dalton or ⁇ 500 dalton.
  • suitable precursor compound can be found amongst organic compounds that have a high content of heteroatoms selected amongst oxygen, nitrogen and sulphur, provided that the other plasma parameters are properly set.
  • high content in this context is meant that the ratio between the total number of the heteroatoms, e.g. oxygen, and the number of carbon atoms should be > 0.1, such as > 0.25 or > 0.5 or > 0.75, in the precursor compound. From theoretical considerations this ratio is never larger than 2.
  • the organic precursor compound have certain properties that one would like to incorporate into a coat but a too low content of heteroatoms, this may be compensated for by including oxygen in the gas plasma.
  • one may include one or more other organic compounds for which the content of heteroatoms is higher than in the desired precursor compound.
  • hydrocarbons and fluorinated hydrocarbons e.g. perfluoinated hydrocarbons (PFH)
  • suitable precursor compounds can be found amongst organic compounds having a low content of heteroatoms selected amongst oxygen, nitrogen and sulphur, provided that the other plasma variables are properly set.
  • a "low content” in this context means that the ratio between the number of heteroatoms, e.g. oxygen, and the number of carbon atom should be ⁇ 0.75, such as ⁇ 0.50 or ⁇ 0.25 or ⁇ 0.10.
  • organic precursor compound have certain properties that one would like to incorporate into a coat but a too high content of heteroatoms, this might be compensated for by including one or more organic compounds for which the content of heteroatoms is lower than in the desired precursor compound.
  • Suitable precursor compounds may also be found amongst organic compounds that contain one, two or more structural units that are present in polymers that are known to give coats that are resistant to non-specific adsorption. These kinds of precursor compounds are in the innovative method combined with gas plasma conditions enabling this property to be retained in the coat deposited on the substrate.
  • Non-ionic and hydrophilic i.e. contains a plurality of neutral hydrophilic groups, such as hydroxy, amido, and lower alkoxy including alkyleneoxy (C ⁇ . 3 in particular C 2 ) and alkyl ether groups.
  • neutral hydrophilic groups such as hydroxy, amido, and lower alkoxy including alkyleneoxy (C ⁇ . 3 in particular C 2 ) and alkyl ether groups.
  • Precursor compounds to be used in this variant of the invention can thus be found amongst low molecular weight compounds that comprise one or more of these structural units that are present in polymers that reduce non-specific adsorption.
  • one of the most promising precursor compounds comprise the structural unit -(CH 2 ) n O-, where (a) n is an integer 1-3, with preference for 2, (b) the free valence at the carbon binds to hydrogen or an oxygen, and (c) the free valence at the oxygen binds to a hydrogen or a carbon.
  • the carbon may be sp 3 -, sp 2 - or sp-hydridised and may thus be part of a saturated or unstarurated hydrocarbon group such as alkyl (for instance CI, C2, C3 to C5) and alkenyl, such as vinyl).
  • alkyl for instance CI, C2, C3 to C5
  • alkenyl such as vinyl
  • n' is an integer 1-10 with preference for 1-5
  • R is lower alkyl (C 1 . 5 ), such as methyl, or lower acyl (C ⁇ - 5 , such as fortnyl or acetyl)
  • the free valences binds to atoms selected amongst hydrogen, carbon, sulphur, nitrogen and oxygen.
  • candidate precursor compounds are monomers or oligomers (2-10, such as 2-5, repeating monomeric units) corresponding to polymers that give coats that have low non-specific adsorption.
  • a coat providing low non-specific adsorption should also have a sufficient hydrophilicity in order to secure a reliable and reproducible transport of reagents by an aqueous liquid flow.
  • candidates of precursor compounds can also be found among the precursor compounds that are candidates for the creation of hydrophilic coats. See above.
  • the thickness of the coat should be ⁇ 50 %, for instance ⁇ 20 % or ⁇ 10 %, of the smallest distance between two opposing sides of a microchannel part comprising the innovative coat.
  • An optimal thickness will typically be ⁇ 1000 nm, for instance ⁇ 100 nm or ⁇ 50 nm, with the provision that the coat shall permit a desired flow to pass through.
  • a lower limit is typically 0.1 nm.
  • preselected wetting/or non-wetting - properties and/or ability to reduce non-specific adsorption anti-fouling. This can be accomplished as outlined in the experimental part that describes the determination of a) liquid contact angles, and b) adsorption of albumin, which is a measure of non-specific adsorption.
  • a reduction in non-specific adsorption refers to bovine serum albumin as a reference/model substance and means that the ratio between adsorption of bovine serum albumin after and before a gas plasma treatment of a surface according to the invention is ⁇ 0.75, such as ⁇ 0.50 or ⁇ 0.25 (decrease ratio). The ratio can be even lower, for instance ⁇ 0.10.
  • Adhering the substrate surfaces to each other (step vi).
  • the substrates are made of inorganic material such as silicon, glass, quartz and the like.
  • the substrate surfaces comprise plastics, the two surfaces can be fixed to each other by pressing the surfaces together while heating selectively the surface not containing microstructures above its transition temperature, while the surface with the microstructures are maintained below its transition temperature.
  • various kinds of adhesives or glues may be used.
  • the microchannel structures are preferably defined by relief patterns that are present in either one or both of the substrate surfaces as outlined in PCT/SE02/02431 (Derand et al).
  • the adhesive may be selected as outlined in US 6,176,962 and WO 9845693 (Soane et al).
  • suitable bonding materials include elastomeric adhesive materials and curable bonding materials. These kinds of bonding material as well as others may be in liquid form when applied to a substrate surface. Bonding materials including adhesives thus comprises liquid curable adhesive material and liquid elastomeric material. After application the adhesive material is rendered more viscous or non-flowable for instance by solvent removal or partial curing before the other substrate is contacted with the adhesive.
  • liquid fo ⁇ n includes material of low viscosity and material of high viscosity.
  • Curable adhesive includes polymerizable adhesives and activatable adhesives.
  • the ⁇ no- curarable, moisture-curable, and bi-, three- and multi-component adhesives are also examples of curable adhesives.
  • This aspect of the invention is primarily characterized in that a part of the inner surface of at least one of the microchannel structures has been modified by the use of gas plasma comprising an organic precursor compound selected according to the principles outlined for the first aspect, i.e. has one or more surface characteristics that is achievable by a plasma polymerisation coating method. Additional characteristic features are defined below.
  • the microfluidic device preferably contains a plurality of microchannel structures, each of which is defined between two or more planar substrates as discussed under the heading "Technical Field".
  • Each microchannel structure may comprise one, two, three or more functional parts selected among: a) application chamber/cavity/area, b) conduit for liquid transport, c) reaction chamber/cavity; d) volume defining unit; e) mixing chamber/cavity; f) chamber for separating components in the sample, for instance by capillary electrophoresis, chromatography and the like; g) detection chamber/cavity; h) waste conduit/chamber/ cavity; i) internal valve; j) valve to ambient atmosphere; etc. Many of these parts may have one or more functionalities.
  • a compound which has been separated, formed or otherwise processed in a microchannel structure are collected and transferred to some other instrument, for instance an analytical instrument such as a mass spectrometer.
  • an analytical instrument such as a mass spectrometer.
  • outlet vents for air Inlets and outlets for liquids may also function as vents (inlet vent or outlet vent).
  • the preferred devices are typically disc-shaped with sizes/surface areas and/or forms similar to the conventional CD-format, e.g. their surface areas are in the interval from 10% up to 300 % of the surface area of a CD of the conventional CD-radii.
  • the upper and/or lower sides of the disc may or may not be planar.
  • the preferred microfluidic discs have an axis of symmetry (C n ) that is perpendicular to the disc plane, where n is an integer > 2, 3, 4 or 5, preferably oo (C ⁇ ).
  • the disc may be rectangular, such as square-shaped, or have other polygonal forms, but is preferably circular.
  • centrifugal force may be used for driving liquid flow. Spinning the device around a spin axis that typically is perpendicular or parallel to the disc plane may create the necessary centrifugal force. In the most obvious variants at the priority date, the spin axis coincides with the above- mentioned axis of symmetry.
  • each microchannel structure comprises an upstream section that is at a shorter radial distance than a downstream section relative to a spin axis.
  • the microfluidic device may also comprise common channels connecting different microchannel structures, for instance common distribution channels for introduction of liquids and common waste channels including waste reservoirs.
  • Common channels including their various parts such as inlet ports, outlet ports, vents, etc., are considered to be part of each of the microchannel structures they are connecting.
  • Common microchannels may also fluidly connect groups of microchannel structures that are in different planes or in the same plane.
  • microchannel structures means two, three, four, five or more microchannel structures.
  • plurality means that the number of microchannel structures on the microfluidic device is > 10, such as > 25 or > 90 or > 180 or > 270 or > 360.
  • microchannel contemplate that a channel structure comprises one or more cavities and/or channels/conduits that have a cross-sectional dimension that is ⁇ 10 3 ⁇ m, preferably ⁇ 0.5 x 10 3 ⁇ m or ⁇ IO 2 ⁇ m.
  • the lower limit for cross sectional dimensions is typically significantly larger than the size of the largest constituent of a liquid that is to pass through a microchannel of the innovative device.
  • the volumes of microcavities/microchambers are typically ⁇ 1000 nl, such as ⁇ 500 nl or ⁇ 100 nl or ⁇ 50 nl or ⁇ 25 nl.
  • Microformat means that one, two, three or more liquid aliquots that are transported within the device are within the intervals specified for the microchambers/microcavities.
  • a polycarbonate CD disc (Macrolon DP-1265, Bayer AG, Germany), and pieces cut from a polycarbonate CD disc were placed in a plasma reactor (CVD Piccolo, Plasma Electronic, Germany), and subjected to argon plasma treatment at 24 W for 2 min. Subsequently, the polycarbonate surfaces were treated with plasma of diethylene glycol dimethyl ether (diglyme; Aldrich, USA) at 24 W for 5 min. The water contact angle (sessile drop) of the resulting surfaces was measured on a Rame-Hart manual goniometer bench. The average of six equilibrium measurements (three droplets) was 48°.
  • a polycarbonate CD disc (Macrolon DP-1265, Bayer AG, Germany), and pieces cut from a polycarbonate CD disc were placed in a plasma reactor (CVD Piccolo, Plasma Electronic, Germany), and subjected to argon plasma treatment at 24 w for 2 min. Subsequently, the polycarbonate surfaces were treated with plasma of diethylene glycol dimethyl ether (diglyme; Aldrich, USA) at 24 W for 5 min. Finally, they were subjected to plasma of allylic alcohol (Merck, Germany) at 12 W for 5 min. The water contact angle (sessile drop) of the resulting surfaces was measured on a Rame-Hart manual goniometer bench. The average of six equilibrium measurements (three droplets) was ⁇ 10°.
  • a polycarbonate CD disc (Macrolon DP-1265, Bayer AG, Germany), and pieces cut from a polycarbonate CD disc were placed in a plasma reactor (CVD Piccolo, Plasma Electronic, Germany), and subjected to argon plasma treatment at 24 w for 2 min. Subsequently, the polycarbonate surfaces were treated with plasma of ethylene glycol vinyl ether (Aldrich, USA) at 12 W for 5 min.
  • the water contact angle (sessile drop) of the resulting surfaces was measured on a Rame- Hart manual goniometer bench. The average of six equilibrium measurements (three droplets) was 22°. Microfluidic test
  • a silicone rubber lid (polydimethylsiloxane) was placed on a polycarbonate CD with recessed microchannel pattern, (50-200 ⁇ m wide, 50-100 ⁇ m deep), that had been treated either with diglyme plasma, or with diglyme plasma with subsequent allylic alcohol plasma treatment, as described above.
  • silicone rubber with recessed microchannel pattern 1000 ⁇ m wide, 100 ⁇ m deep was placed on flat polycarbonate surfaces that had been treated either with diglyme plasma, or with diglyme plasma with subsequent allylic alcohol plasma treatment, as described above.
  • Resulting flow channels were examined using a solution of Cibacron Brilliant Red (CTBA limited) in MilliQ water (Millipore). A drop was placed at the channel inlet and it was concluded that flow rate into channels on surfaces that had been subjected to diglyme plasma with subsequent allylic alcohol plasma treatment was significantly higher than on surfaces that had only been treated with diglyme plasma.
  • CBA Cibacron Brilliant Red
  • Bovine serum albumm (BSA; fraction V, Sigma, USA) was chosen as model protein for adsorption studies, and labelled with fluorescein-5-isothiocyanate (FITC; isomer I; Molecular Probes), as described in [Lassen, B. and Malmsten, M., Competitive protein adsorption studied with TIRF and ellipsometry. Journal of colloid and interface science, 1996. 179: p. 470-477].
  • the molar ratio of FITC to proteins was found to be approximately unity in all cases.
  • a TIRF fluorescence intensity graph resulting from adsorption of 400 ppm FITC-BSA on untreated polycarbonate (PC) is shown in figure 1, together with a graph representing the same experiment on a diglyme plasma-treated surface.
  • TIRF fluorescence intensity graphs using diglyme plasma + allylic alcohol plasma (figure 2), and ethylene glycol vinyl ether plasma (figure 3) are also presented here. It is apparent from the figures that the ratio between adsorption of protein on the treated surface and the untreated surface always is ⁇ 0.25.
  • Protein solution (400 ppm) enters the flow cell (filled arrow) and is replaced by PBS buffer (dashed arrow).

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Abstract

L'invention concerne un disque microfluidique comprenant au moins une structure à microcanaux fermée, chacune comprenant une section définie entre deux substrats sensiblement planaires (I et II). Une surface de l'un ou de l'autre substrat comprend des microstructures sous formes de rainures et/ou de saillies s'adaptant les unes aux autres qui, ensemble, définissent au moins une structure à microcanaux lorsque les deux surfaces sont opposées dans le dispositif microfluidique. Lesdites structures sont conçues pour transporter des liquides. Ledit dispositif se caractérise en ce qu'au moins une partie des parois internes de la section de chaque structure à microcanaux comprend un revêtement déposé par traitement au moins de la partie correspondante de l'une ou de l'autre surface au moyen d'un plasma gazeux comprenant au moins un composé précurseur organique. L'invention concerne également un procédé de production du disque en question.
EP03710598A 2002-04-09 2003-04-07 Dispositifs microfluidiques dotes de nouvelles surfaces internes Withdrawn EP1492724A1 (fr)

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US37108002P 2002-04-09 2002-04-09
SE0201086A SE0201086D0 (sv) 2002-04-09 2002-04-09 Microfluidic devices with new inner surfaces
US371080P 2002-04-09
SE0201086 2002-04-09
PCT/SE2003/000560 WO2003086960A1 (fr) 2002-04-09 2003-04-07 Dispositifs microfluidiques dotes de nouvelles surfaces internes

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EP1594798B1 (fr) 2003-01-30 2018-12-19 Gyros Patent Ab Parois interieures de dispositifs microfluidiques
SE0403139D0 (sv) * 2004-12-23 2004-12-23 Nanoxis Ab Device and use thereof
EP1848996A4 (fr) 2005-01-17 2009-12-02 Gyros Patent Ab Procede permettant de co-transporter un reactif avec une substance macromoleculaire amphiphile dans un conduit de transport microfluidique
WO2006110095A1 (fr) 2005-04-14 2006-10-19 Gyros Patent Ab Dispositif microfluidique comprenant des valves digitiformes
US7556776B2 (en) 2005-09-08 2009-07-07 President And Fellows Of Harvard College Microfluidic manipulation of fluids and reactions
DE102007018383A1 (de) * 2007-04-17 2008-10-23 Tesa Ag Flächenförmiges Material mit hydrophilen und hydrophoben Bereichen und deren Herstellung
WO2009134395A2 (fr) 2008-04-28 2009-11-05 President And Fellows Of Harvard College Dispositif microfluidique pour un stockage et un agencement bien défini de gouttelettes
GB2471271A (en) * 2009-06-19 2010-12-29 Univ Dublin City Method of coating the channels of a microfluidic device
CN104837492B (zh) 2012-12-07 2018-04-27 糖模拟物有限公司 使用e-选择素拮抗剂动员造血细胞的化合物、组合物和方法
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