Patent Application
20090221082
The invention relates to a microfluidic device and to a process involving used of the device. The device comprises a membrane allowing evaporation. The process involves performing a measurement or observation of compounds introduced in the device.
Determination of the phase diagram of multicomponent systems is of importance in many realms: industrial formulation, protein cristallization, bottom up material assembly from spontaneous ordering of surfactant, polymeric or colloidal systems. Methods to reach this goal include thermal variations (in space or time) of samples of fixed concentrations or isothermal concentration by either removal of the solvent (osmosis, drying) external action on the solutes (sedimentation or dielectrophoresis for colloids), or studies of spontaneous interdiffusion in contact experiments. Depending on the application, one may want to access only the equilibrium phase diagram or gain additional information as to the metastable phases that can appear for kinetic reasons.
The invention introduces microfluidic tools for controlled isothermal concentration of a wide range of systems, covering solutions of ions, polymers, proteins, surfactants and colloidal suspensions.
The invention allows performing precise measures and/or sets of measures, and/or allows performing rapid measures and/or sets of measures, and/or allows performing simple measures and/or sets of measures, and/or performing measures and/or sets of measures with low amounts of matter.
The invention relates to a monolayered or multilayered device comprising:
at least one elongated flowing channel (1, 21a, 21b, 41a, 41b, 61a, 61b, 71, 81), for flowing a liquid therein, having a length and a width and/or depth, in a first layer, said channel having a closed section,
at least one evaporating chamber (2, 72, 82), for flowing a gas therein, in a second layer, said chamber having a closed section, or at least one evaporating open-air zone (42, 62),
the evaporating chamber or zone surrounding the width and/or depth of the channel, along at least ⅓ of the length, preferably at least ½, preferably at least ⅔, and/or along at least 10 times the width and/or depth of the flowing channel, preferably at least 100 times,
the flowing channel and the evaporation chamber or zone being separated by an evaporation membrane (3, 43, 73, 83).
The device is preferably a microfluidic device.
The length of the flowing channel(s) is preferably of at least 100 times its width and/or depth.
The closed cross section of the flowing channels can be for example comprised of 4 elongated walls defining width and depth in the section plan, and length in the elongation plan.
The device preferably comprises at least one microfabricated element (4a, 4b). The microfabricated element can be comprised of:
an elastomeric material, such as a silicone such as polydimethylorganosiloxane (PDMS), or
a non elastomeric material such as a metal or glass, or non elastomeric plastic.
Microfabrication techniques and materials are know by the one skilled in the art, especially in the field of microfluidics.
A closed evaporation chamber is typically provided with a multilayered device. An evaporating open air zone is typically provided with a monolayered device. Typically a multilayered device associates several layers of microfabricated elements. The association can be performed by bonding a microfabricated element onto the other, for example by pasting or welding. Typically a monolayered device has a single microfabricated element.
The evaporating chamber or zone surrounds the width and/or depth of the channel. By surrounding it is meant that the chamber or zone is close to the flowing channel(s) and that for at least one segment of the flowing channel(s), said flowing channel(s) and the evaporation chamber or zone are separated by an evaporation membrane or a part thereof. The surrounding can be also referred to a covering. However it is possible to have the evaporation chamber or zone on top of the flowing channel(s) as shown on
The evaporations chamber has preferably two channels allowing a gas inlet and a gas outlet.
For examples the device can comprise a first layer and an optional second layer, wherein:
the first layer comprises a first microfabricated element comprising the evaporation membrane and the flowing channel(s) carved into said first element, closed with a support plate (5) such as a glass or metal plate,
the optional second layer comprises a second microfabricated element comprising the evaporation chamber(s) carved into said second element, closed with the evaporation membrane of first layer.
The evaporation membrane is typically a part of a microfabricated element. It is preferred that the evaporation membrane be substantially not deflectable and is not deflected during the use of the device. Deflection can be controlled by managing the thickness of the membrane and/or its material. Deflection can be also controlled by managing the dimensions of the flowing channel(s) for example by using a channel(s) with a low with and/or depth is the segment surrounded by the evaporation chamber or zone. Deflection can be also controlled by managing the gas flow and/or the gas pressure. Upon flowing a gas deflection of the membrane should be avoided in order to prevent stopping a flow in the flowing channel(s).
The evaporation membrane typically closes a part of the section of the flowing channel(s) and of the evaporation chamber, and/or closes a part of the section of the flowing channel(s) and defines the evaporation zone.
It is preferred that the evaporation chamber(s) or zone(s) be elongated and substantially parallel to the flowing channel(s).
The flowing channel(s) can have a width and/or depth of less than 10 μm, preferably of less than 5 μm.
The flowing channel(s) can have a length of more than 1 mm, preferably of more then 5 mm, preferably of more than 10 mm.
The evaporation membrane can have a thickness of lower than 100 μm, preferably of lower than 50 μm.
The evaporation chamber(s) or zone(s) is preferably an elongated channel, open-air or closed, having a length and a width and/or depth, the width and/or depth being higher than the width and/or depth of the flowing channel(s).
In one embodiment the device comprises:
at least two flowing channels (21a, 21b or 41a, 41b, or 61a or 61b), being parallel on at least one segment thereof,
a single evaporation chamber (22) or zone (42, 62) surrounding the at least two flowing channels, or at least two evaporation chambers or zones, preferably evaporation channels, surrounding each at least one of the flowing channels.
In this embodiment the at least two flowing channels can have each a different length surrounded by the evaporation chamber(s) or zone(s).
The device can further comprise means for providing heat, such as means for heating a gas introduced into the evaporation chamber(s) or zone(s), said heat being optionally provided as a constant or as a gradient along at least a part of the channel(s). The device can thus comprise means for flowing a gas into the evaporation chamber or zone. For example the evaporation chamber can be connected to a gas dispenser such as a bottle with a vane, with a gas heater. The temperature of the gas is preferably controlled and/or measured.
The device typically comprises means (6) for providing a liquid into the flowing channel(s). Examples of such means include a reservoir or a syringe. The reservoir can be filled with any appropriate mean, such as a syringe, a bottle, a pipette, a capillary tube etc. . . . .
Typically the flowing channel(s) has:
an introduction extremity, linked to means (6) for providing a liquid into the flowing channel(s), and
an ending extremity, being linked to means for recovering matter comprised into the channels, or preferably being a blind extremity (7, 31, 51, 63a, 63b, 74, 84).
In one mode the flowing channel(s) does not extend beyond the evaporation chamber(s) or zone, has a blind extremity surrounded by the evaporation chamber(s).
In another mode the flowing channel(s) extends beyond the evaporation chamber(s) or zone (3), and has a blind extremity not surrounded by the evaporation chamber(s) or zone (s).
In one particular embodiment:
the flowing channel(s) extends beyond the evaporation chamber(s) or zone(s), and has a blind extremity not surrounded by the evaporation chamber(s) or zone(s), and
the flowing channel(s) have an enlarged blind extremity forming an accumulation chamber (31, 51, 63a, 63b, 74, 84), not surrounded by the evaporation chamber(s) or zone(s).
By “enlarged” it is meant the blind extremity has a width and/or depth substantially higher than the width and/or depth or the flowing channel(s), preferably of at least 5 times higher. In one mode the accumulation chamber is enlarged only for its depth or width. It can be referred to a 2-dimensionnal accumulation chamber (31, 51, 63a, 63b). In another mode the accumulation chamber is enlarged for its depth and its width. It can be referred to a 3-dimensionnal accumulation chamber (74, 84). 3-dimensionnal accumulation chambers can allow accumulating more composition of matter, and can allow having much more composition of matter there than in the flowing channel(s).
The accumulation chamber is usually not connected to means for removing matter therefrom. Once compositions of matter have accumulated there and once measures and/or observations have been performed, the device (or at least the part of the device comprising the flowing channel(s)) is usually disposed of. There is usually no connection from the accumulation chamber to out of the device, except via the flowing channel(s). On the contrary for example a reservoir is connected to the flowing channel and to out of the device (for example with an open-air opening as represented to the figures).
In one embodiment the flowing channel(s) has two introduction extremities, both being linked to means for providing a liquid into the each of the extremities of the flowing channel(s). Such means include reservoir, syringes etc. . . . .
Usually the device will comprise means for mixing at least one chemical compound and a carrier liquid to be at least partly evaporated along the channel(s), upstream the flowing channel. Conventional pots and/or mixers can be used. In one embodiment the device can be associated to a microfluidic mixing device allowing providing a range of concentrations of mixture along time, and/or topography, for example comprising several mixing output channels, connected to several flowing channels, for example a Whitesides-like Microfluidic mixing device.
According to a specific embodiment the device has:
at least two flowing channels, and
at least one open-air evaporation zone, or
at least two flowing channels, and
at least one closed evaporation chamber.
According to a specific embodiment the device has:
at least one, preferably at least two, accumulation chamber(s) which is not surrounded by an evaporation membrane, and
at least one open-air evaporation zone, or
at least one, preferably at least two, accumulation chamber which is not surrounded by an evaporation membrane, and
at least one closed evaporation chamber.
The invention also relates to a process for determining physical and/or chemical properties of chemical compounds or mixtures of chemical compounds, comprising the steps of:
a) providing:
Typically the flowing in step b) can be induced by removal of the carrier fluid, the flowing being optionally stopped upon solidification of the mixture (dynamic movement of carrier fluid). Without being bound to any theory, it is believed that motion (flow) of the liquid in the flowing channel(s) is induced by evaporation of the carrier. The liquid can flow to an extremity of the flowing channel(s), optionally to an accumulation chamber. Alternatively the liquid can flow in a part the flowing channel(s), to a point where is solidifies completely, beyond which there is no flowing. Complete solidification can be due to a lack of a sufficient amount of carrier further to evaporation. Preferably substantially no movement of fluid is induced in the accumulation chamber, if the device has such a chamber, and the concentration of carrier fluid in the chamber being of zero or higher.
It is preferred that the carrier fluid be chemically compatible with the channel(s) material(s) and the evaporation membrane material(s), and such that the membrane/carrier system allow transfer of the carrier trough the membrane (for example by having appropriate membrane thickness, porosity and/or material). Compatibility means that the carrier fluid should not chemically degrade to flowing channel(s)'s and membrane's material, and should not be repelled by the membrane's material.
The liquid mixture comprises a carrier and one or several candidate chemical compound(s). In the embodiment where the liquid mixture comprises several candidate compounds, these several compounds can represent a mixture and/or association and/or reagents, that is to be studied and/or screened via the measurement and/or observation.
The gas flow is provided by appropriate means. The gas flow is at a temperature and/or at a flow rate allowing evaporation of the carrier and removal thereof from the evaporation chamber or evaporation zone. Open air contact might provide enough heat and movement to do so.
In step a) a liquid is provided in the flowing channel(s). The liquid is typically by appropriate means, for example by a reservoir. The liquid is thus a placed at an inlet(s) of the flowing channel(s).
The candidate chemical compound(s) can form a solid along the channel(s), said solid being:
In one embodiment the compositions of matter are varied, in space along the channel(s) and/or in time at one point along the channel(s), by varying the gas flow characteristics, such as stopping and/or re-starting the gas flow or varying the speed flow, or varying the temperature. It is believed that varying the gas flow characteristics, controls distribution of solids and/or concentrated phases in the carrier fluid, allows for example relaxation and/or diffusion of solids back along the flowing channel(s) upon lowering or stopping evaporation flow (lowering gas flow and/or stopping gas flow and/or lowering temperature).
In one embodiment:
the device has an accumulation chamber,
the candidate compound(s) forms a solid and/or a concentrated phase along the channel(s) that accumulates in the accumulation chamber, and
a flow of solids in time and/or in space is controlled, as diffusion of solids back in the channel is controlled.
In one embodiment the composition of matter in the accumulation chamber varies along time, for example the concentration varies (usually increasing by accumulation).
It is believed that the accumulation chamber can help in addressing diffusion artifacts when several candidate compounds are present in the liquid. One would typically perform measurements and/or observations at the accumulation chamber, and optionally at the border thereof, in the flowing channel(s) just before the accumulation chamber. The amount of a solute candidate compound in the accumulation chamber vis a vis the amount in the flowing channel can be determined. If two solute candidate compounds are introduced in a known ratio in the flowing channel, then the same ratio will be retrieved in the accumulation chamber, without possible diffusion artifacts that can be observed in the flowing channel. The accumulation chamber can thus improve precisions of measurements, observations and/or datas obtained from computations therefrom.
In one embodiment one can perform a first measure in the accumulation chamber at time t1 with a proportion of carrier fluid of c1, and then perform at least one second measure in the accumulation chamber at time t2 with a proportion of carrier fluid of c2 being lower than c1 (as matter accumulates). One would then compute the measures to determinate a useful property or parameter.
In one embodiment one can introduce first in the flowing channel a mixture of candidate compounds A and B with relative proportion of respectively a/(a+b) and b/(a+b) then one can perform a measure in the accumulation chamber for said proportions, then one can introduce a second proportion of a′/(a′+b′) and b′/(a′+b′), and then perform a measure in the accumulation chamber for proportions respectively of (a+a′)/(a+a′+b+b′) and (a+a′)/(a+a′+b+b′). One would then compute the measures to determinate a useful property or parameter.
In one embodiment the device comprises at least two flowing channels (21a, 21b), being parallel on at least one segment thereof. In one aspect of this embodiment the device can have accumulation chambers associated with the flowing channels, and one can perform the following:
first step:
optionally, then second step:
In another aspect of the embodiment one liquid mixture being provided into one of the flowing channels is a reference liquid mixture, having a known physical and/or chemical property. One would typically measures a property for one or several channel(s) having a candidate compound and compare it to a measure performed for the channel having the reference liquid mixture. One would compute to measures and/or comparison to determine a useful property or parameter.
In still another aspect of the embodiment:
the at least two flowing channels have each a different length surrounded by the evaporation chamber(s) (the evaporation can have a constant length with flowing channels having different lengths as shown on
the same liquid mixture is introduced in at least the two channels,
concentration in carrier fluid has a different rhythm in the different channels, and
a solid and/or a concentrated phase forms at different rhythms in the different channels.
The rhythms refer to formation of a solid or concentrated phase as of time and/or space along the channels. The different rhythms can be used to generate information about solubility and/or crystallization kinetics and/or crystal growth kinetics.
In still another aspect of the embodiment two different liquid mixtures (for example as of chemical compositions and/or concentrations) of an identical or different carrier fluid and one or several (for example mixture and/or association and/or reagents) identical or different candidate chemical compound(s) are flowed into the flowing channels. The different liquid mixtures, can be provided with an associated microfluidic mixing device. One can thus generate information about the different mixture and candidate compounds and associations/reactions/interactions thereof or therewith. In one particular fashion:
the carrier fluid is identical in each channel,
the candidate chemical compound(s) are different in each channel and/or are mixtures of identical compounds with different concentrations in each channel, and
the process provides an array of:
In another particular fashion:
the carrier fluid is different in each channel,
the candidate chemical compound(s) is identical in each channel and/or are mixtures of an identical compound with another compound, optionally with different concentrations, and
the process provides an array of:
The measurements and/or observations can be performed by any appropriate means, methods, and techniques. These include conventional techniques used in chemistry, physics and physico-chemistry, including those more recently developed for microfluidics. For example one can implement spectroscopy (for example Raman, Infra-red, UV), fluorescence, conductimetry, rheology measures (for example with using magnetic particles) and/or optical observations (usually with a microscope, optionally using a polarizer), preferably by image analysis. The measurements and/or observations can be are computed, optionally with using all or a part of the process parameter (flow rates, concentrations, natures of compounds) to provide:
phase diagrams, such a binary, tertiary or further phase diagrams,
crystallization diagrams,
crystallization kinetics datas,
crystal growth kinetics datas,
solubility datas,
nucleation of solids datas,
kinetics of chemical reactions,
formulation information, for example in the field of pharmaceuticals, cosmetic compositions, detergent compositions, coating compositions, and/or
material engineering datas, for example for engineering inorganic compounds, or for engineering polymeric compounds.
The candidate chemical compound(s) can comprise:
biological molecules, for example biological polymers, and/or
non biological molecules, for examples synthetic polymers, surfactants, inorganic particles.
In some embodiments the carrier fluid is a solvent or at least some of candidate chemical compounds, the mixture of the carrier fluid being and the candidate being in a form of:
The invention also relates to a process of screening candidate compounds, comprising a process described above, and/or comprising the step of introducing the candidate compounds in the device above. One would typically performs measurements and/or observations one several compounds or mixtures of compounds and then identified a useful compounds or mixture of compounds for an optimum property.
Further details, embodiments, and/or advantages of the invention appear on the following examples which are not limitative.
It is found that in standard microsystems built of PolyDiMethylSiloxane (PDMS), spontaneous water permeation through the PDMS matrix induces flows that can be used to concentrate colloids. We have engineered specialized microgeometries that allow us to control spatially and temporally the evaporation process as well as the resulting concentration of solutes.
After a brief description of the micro-devices, we demonstrate first our control of the concentration process on dilute aqueous solutions of fluorescein and nanoparticles. We then report controlled nucleation and growth of crystals of potassium chloride (KCl) in micro-channels, and extract various thermodynamic quantities (solubility, crystal density) as well as kinetic features (sensitive to the rate of concentration). After a discussion of the large spectrum of experiments that can be performed in similar microfabricated devices, we conclude on the versatility and large applicability to soft matter systems.
The devices used are two-layer PDMS on glass Microsystems (
General processes for preparing multilayer microfluidic devices are for example described in document WO 01/01025, which is incorporated by reference. These processes can be adapted simply to obtain the geometry (topography, design, length, width, depth, etc. . . . ) of the present invention.
To quantify the induced flow, we adapt the analysis, anticipating that evaporation occurs here mostly through the thin membrane, at a volumic flow rate of water ve (it has dimension of a velocity). Mass conservation then sets the height-averaged velocity in the microchannel: v(x)=−ve(x/h). Its amplitude rises with the distance x from the dead-end (x=0) up to v0=ve(L0/h) at the end of the evaporation zone (x=L0). v(x)=−v0 in the evaporation-free section of the finger L0≦x≦L.
With our dedicated systems we induce large values of ve (in the 50 nm/s range) due to the thin membranes (permeation yields a limit scaling as 1/e) and to the dry air flown through the top network (velocities of order cm/s) that reduces the diffusive boundary layer. More importantly, we gain a spatial and temporal control on ve by designing the geometry (evaporation is negligible but for chosen locations) and by tuning in time the air flow and thus ve. Quantitative temporal control of the flow field is clear from the motion of tracers at a given location as the air flow is successively turned on and off (
When on, tracer velocities of order 13 μm/s are observed, corresponding to
Control of the flow field translates into that of the induced concentration process. For the simplest case of a dilute species of diffusion coefficient D in a finger, in a one-dimensional description the conservation equation dtc+dxJ=0 relates the concentration c(x,t) and flux J(x,t)=cv−Ddxc. We focus now on steady evaporation and thus constant v(x) in time, with a reservoir at fixed concentration c0. The physics at work is simple: the flow convects the solute towards the dead end where it accumulates. The current of solute injected into the finger is steady J0=c0v0. Backwards thermal diffusion against the flow controls the width of the accumulation zone, which is p=(Dh/ve)1/2=(D
c(x,t)=c0v0t(2/p2π)1/2 exp(−x2/2p2)+c0R(x) (1)
with R(x)≈L0/x for p<<x<<L0. Experiments on solutions of fluorescein and nanocolloids quantitatively support this analysis (
Concentration at the tip increases as dc(x=0)/dt=(2/π)1/2(ve/h)3/2c0L0D−1/2, offering many means of kinetic control of the process: through geometrical features L0, h and e (that affects ve), and through operational parameters c0 and ve. The latter can be modulated during an experiment, which allows us to pinch or relax concentration profiles, at a diffusion-limited response time ˜p2/D=h/ve=
This control permits the study of phase transitions as we now show on a well characterized system, KCl aqueous solutions. We use a microchip with multiple “fingers” of different lengths L0 originating from the same reservoir, and perform a few experiments, at the same steady air flux, with different initial concentrations. Upon concentration, we observe in each finger the nucleation of crystals close to tip, at xc and tc (
Nucleation occurs at tc˜K (c0L0)−1, which from (1) suggests a nucleation concentration cc=K√(2/π).D−1/2
This demonstrates a possible use of our devices. Feeding a few fingers with a system of reference (e.g. KCl or fluorescent probes) provides a local calibration of the value of
Further, with our microdevices we can investigate the influence of the kinetics of the concentration process on the morphologies and phases produced. We indeed observe on KCl solutions that both the nucleation scenario and the crystal growth process vary when the initial concentration c0 and thus the concentration rate are changed. In the studies reported above, we reproducibly observe demixing of the solution into what looks like droplets in front of the growing crystal, but only at the lowest initial concentration examined (
Benefits from Microfabrication
We have shown how microfabrication provides us with control, through flexibility in the geometrical parameters (e, h, L0, L), and by permitting time regulation. In addition, the following can be done:
Beyond ionic solutions and colloids, the invention can be used on on surfactant solutions and on biomaterial crystallization. Experiments on Sodium Dodecyl Sulfate (SDS), allows to observe sequences of many different mesophases in a given microchannel (
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/009645 | 10/5/2006 | WO | 00 | 10/8/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60724127 | Oct 2005 | US |
