Note: Descriptions are shown in the official language in which they were submitted.
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TITLE
A MICROFLUIDIC METHOD AND STRUCTURE WITH AN ELASTOMERIC GAS-
PERMEABLE GASKET
CROSS REFERENCE TO RELATED APPLICATIONS
[001] This application claims priority to U.S. Provisional S/N 60/765,150 for
"Rigid
Microfluidic Device with an Elastomeric Gas-Permeable Gasket" filed on
February 3, 2006; U.S.
Provisional S/N 60/791,778 for "Rigid Microfluidic Device with an Elastomeric
Gas-Permeable
Gasket" filed on April 13, 2006, and claims priority to PCT US/2006/034083 and
is a
continuation in part of U.S. Application No. 11/514,396 for "Method and
Apparatus for the
Mechanical Actuation of Valves in Fluidic Devices" filed on August 30, 2006,
all of which are
incorporated herein by reference in their entirety.
BACKGROUND
Field
[002] The present disclosure relates to the fabrication and assembly of
microfluidic devices. In
particular, a method and apparatus are disclosed wherein the elastomeric layer
is a gas-permeable
gasket without features.
Description of Related Art
[003] Recent developments in the mechanical actuation of microfluidic valves
have
demonstrated that closing valve membranes against hard surfaces may be more
efficient than that
against soft surfaces. Most parts of an elastomeric microfluidic device do not
need the
elastomeric properties (i.e. elasticity, gas permeability, traiisparency).
Some parts may only need
chemical inertness, while others may only require transparency. Thus, by
decreasing the
thickness of the elastomeric layer in a microfluidic device, valve closing by
mechanical actuation
onto the proximal hard layer is more efficient. Furthermore, it results in a
microfluidic device
that can withstand higher forces, higher pressures and does not leak. Although
devices
combining rigid and soft materials have been reported, (Lai, S. M et al. Chem.
Cornmun, 2003,
218-219; Yamamoto, T. et al. Lab Chip, 2002, 2, 197-202) they have not been
designed from
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the standpoint of material requirements and were used in much less demanding
applications than
radiosynthesis
[004] At present, there are several materials that possess properties
necessary for microfluidics,
however, the curing profile of these materials is such that as soon as it is
hard enough to
manipulate, the material is already cured past the point at which
polymerization of the layers to
be bonded could take place. Current methods require several curing steps and
not many
inaterials can afford such repeated curing, leaving a limited number of
possible materials to use.
The most well known methods of microfluidic fabrication rely on molding
individual layers and
then assembling them together (Psaltis, D. et al. Nature, 2006, 442, 381-386).
Microfabrication
of elastomeric materials is further complicated by the necessity to handle
partially-cured polymer
during intermediate steps of the process.
[005] There are several new materials under development that surpass well-
known PDMS
(polydimethylsiloxane) in their chemical resistance. Use of these materials in
place of PDMS
will undoubtedly broaden the utility of microfluidics within a range of
applications. New
materials, however, require the development of novel handling methods that
allow precise
microfabrication of features in under-cured polymers and layer-to-layer
adhesion. These two
parameters alone are non-trivial and preclude many new applications in
microfluidics.
[006] In view of the present art, what is needed is a microfluidic device that
circumvents the
complicated and precise microfabrication of features in under-cured polymers
as well as the task
of layer-to-layer adhesion to provide a microfluidic device that is can be
fabricated reproducibly
and has utility amongst a range of reaction chemicals, while having a tight
seal and being
durable.
SUMMARY
[007] In a first aspect of the present invention, a fluidic structure is
disclosed, said fluidic
structure comprises a first layer (30); a second layer (40) contacting said
first layer, said second
layer being flat, flexible, gas permeable and featureless; a third layer (60)
contacting said second
layer; at least one fluid channel (50), said at least one fluid channel
positioned in the first layer;
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at least one valve pin hole (20), said at least one valve pin hole passing
through the third layer
and stopping at the second layer; at least one pin (10), wherein the at least
one pin is activatable
to actuate the second layer to occlude the at least one fluid channel.
[008] In a second aspect of the present invention, a fluidic structure is
disclosed, said fluidic
structure comprises a first layer (30); a second layer (40) contacting said
first layer, said second
layer being flat, flexible, gas permeable and featureless; a third layer (60)
contacting said second
layer; at least one fluid channel (50), said at least one fluid channel
positioned in the first layer;
at least one valve pin hole (20), said at least one valve pin hole passing
through the third layer
and stopping at the second layer; at least one pin (10), wherein the at least
one pin is activatable
to actuate the second layer to occlude the at least one fluid channel, and at
least one mechanical
means for assembling the first, second and third layers such that the first,
second and third layers
form a monolithic fluidic structure.
[009] In a third aspect of the present invention, a method of fabricating a
fluidic structure is
disclosed, said method comprising the steps of forniing a first layer (30);
forming a second layer
(40) contacting said first layer, said second layer being flat, flexible, gas
permeable and
featureless; forming a third layer (60) contacting said second layer; fornming
at least one fluid
channel (50) positioned in said first layer; forming at least one valve pin
hole (20); providing at
least one pin (10); and providing a means of actuating the at least one pin in
order to actuate the
second layer to occlude the at least one fluid channel.
[010] In a fourth aspect of the present invention, a method of fabricating a
fluidic structure is
disclosed, said method comprising the steps of forming a first layer (30);
forming a second layer
(40) contacting said first layer, said second layer being flat, flexible, gas
permeable and
featureless; forming a third layer (60) contacting said second layer; forming
at least one fluid
channel (50) positioned in said first layer; forming at least one valve pin
hole (20); providing at
least one pin (10); providing a means of actuating the at least one pin in
order to actuate the
second layer to occlude the at least one fluid channel, and providing at least
one mechanical
means for assembling the first, second and third layers such that the first,
second and third layers
form a monolithic fluidic structure.
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[011] One advantage of the present disclosure is that in addition to improved
fluid control, the
disclosed microfluidic device and methods thereof, obviates the problems
associated with
microfluidic devices of the prior art which include limited types of
materials.
[012] Most known -methods of microfluidic fabrication rely on molding
individual layers and
then assembling them together. The method proposed here can reduce the number
of curing
steps to one. All the elastomer-related functions are confined within one
layer that is without
features. The features (e.g. fluid channel, vent channel, etc) are fabricated
within the hard layers
that can be made from a variety of materials including glass and silicon with
minor modifications
of the procedure. It is not imperative that the third (upper) hard layer is
chemically resistant
since it does not come in contact with the reagents. Thus, the present
invention obviates the
inhibiting material restriction irnposed on valve-carrying microfluidics of
the prior art.
Brief Description of the Drawings
[013] Figure 1 shows a vertical cross-section of a gasket chip according to
the present
disclosure.
[014] Figure 2 shows a top-view schematic of fluidic structure having a 6-
valve pin hole (20)
arranged in a symmetrical radial pattern, with 6 corresponding fluid channels
(50) further
comprising a vent channel (110) having an input (115) and an output (120).
[015] Figures 3A-B. Figure 3A shows a"thick" pin valve in prior designs.
Figure 3B shows the
"thin" pin valve of the present disclosure.
[016] Figure 4 shows a"gap ' valve design wherein the fluid channel comprises
a raised feature
(250) opposite of the valve for meeting the pin upon actuation of the second
(gasket) layer (40).
[017] Figure 5A shows a cross section of a gasket chip assembled by mechanical
means-using,
for example, screws (270). Figure 5B shows a cross section of a gasket chip
assembled by
mechanical means-using, for example, clamps (310).
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[018] Figures 6A-F. Figure 6A shows vent and flow layers cast on wax molds and
cured to an
eiastomer-like state. Figure 6B shows soft vent (235) and flow layers (230)
removed from
molds, followed by hole punching and pin insertion. Figure 6C shows thin
elastomeric gasket
layer cast on a flat surface (215) and partially cured. Figure 6D shows the
flow layer placed on
top of the gasket layer. Figure 6E shows the molded layers after cutting the
excess thin layer,
two layers are pulled off the casting surface and inverted. Figure 6F shows
after the addition of
the vent layer on top of the gasket layer, the assembly is cured to
completion.
[019] Figures 7A-F show the step-wise fabrication of a microfluidic device
using sacrificial
"inverse" molds.
[020] Figures 8A-D show the step-wise fabrication of a microfluidic device
using elastomeric
"tub" molds.
DETAILED DESCRIPTION
[021] A rigid microfluidic device with a thin elastomeric gasket layer allows
for efficient
mechanical actuation of fluid channels. In addition, a thin elastomeric gasket
does not absolutely
require adhesion between the layers. When a gasket is clamped between two hard
layers with
sufficient force, the chip acts as a monolithic device that does not allow
leaks or unwanted
channel connections at fluid pressures in excess of 40 psi and at elevated
temperatures up to 100
C.
[022] A new method is disclosed herein for fabrication of a microfluidic
device that results in a
sealed apparatus that is easily reproducible and durable. This microfluidic
device can be
mechanically held together rather than chemically adhered. A microfluidic
device as described
herein comprises a middle "gasket" layer positioned between at least two hard
outer layers. This
gasket layer is sufficiently deformable (e.g. flexible or elastic) to form a
fluid-tight seal against
the outer layers, acting essentially as an 0-ring between the other two
layers.
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[023] The method of the present disclosure, involves the technology suitable
for fabrication of
microfluidic devices based on a reactor with mechanically-actuated valves. In
one embodiment,
the microfluidic device (also referred to as a"chip ') comprises at least
three layers, as follows:
(1) a first rigid layer (30) with the fluidic network etched or molded in it;
(2) a flat second
(middle) gasket layer (40) of gas-permeable elastomer without, bridging over
the features of the
first layer; and (3) a hard third layer (60) with vent features and sleeves
for mechanical valve
actuators (Figure 1).
[024] The layers of a device according to the present invention, can be bonded
by well-known
bonding methods, or held together by mechanical means as opposed to chemical
means. A
combination of both mechanical and chemical means for layer assembly is also
possible. For
mechanical assembly, for example, the layers can be bolted or clamped
together. The outer two
layers should be rigid enough to transfer the mechanical clamping force to the
interface between
the gasket layer and each of the outer layers, and to prevent collapse of
intricate channel features
molded in their surfaces. And, as discussed above, the gasket layer should be
flat, deformable
(e.g. flexible or elastic) to form a fluid-tight seal against the proximal
layers, featureless and gas
permeable in order to acconunodate the solvent exchange requirement of the
device.
[025] Figure 2 contains the top view of a chip having 6 valve pin holes (20)
with 6
corresponding fluid channels (50). Vent channel (110) allows for the
evaporation of solvents
across the second gasket layer membrane. Figure 1 demonstrates the vertical
cross-section of the
same device taken through the middle. It illustrates that all the elastomer
properties required for
an operational chip can be concentrated in the single flat thin layer without
any features and
therefore not requiring elastomeric microfabrication (is this sentence true?).
The lower (first)
layer (30) and the upper (third) layer (60) are hard, rigid layers. The middle
soft "gasket" layer
is without features. Thus, all features (fluid channel, reaction area, vents,
fluid reservoir, etc)
are within the rigid hard layers. This design allows for the gasket layer to
be without features,
and thereby does not limit the necessary thickness required of the gasket
layer for fitnction.
[026] With a thin elastomer gasket layer, actuation of the pin-valves
stretches the elastomer
gasket layer against the hard curved surface of the fluid channel as the fluid
channels goes from
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an open (10) state to closed (11). Fluid reservoirs (91) are also a feature of
the assembled device,
and are below the gasket layer (40). If the lower first layer is etched in
glass or silicon, the fluids
can be introduced via needles (116) that puncture the gasket. Alternatively,
if the first lower
layer is made of a hard polymer the fluid inlets can be formed by hollow metal
pins introduced
into the polymer during molding. The vent (110) in the third upper layer is
separated from the
reaction chamber (90) by the gas permeable membrane (gasket layer). As
mentioned, given the
elastomer layer has no features, this elastomer membrane can be made as thin
as it can be
without breaking. In other words, the gasket layer is not limited in thickness
by other features
contained in the layer.
Valves
[027] Valves of the prior art, (Figure 3A) had to compress 200-600 um of
polymer in order to
close a 45 u.m channel. This design resulted in excess stress leading to
failure by tearing.
Furthermore this design required higher pressures, yet the designs could not
withstand the
increased pressures. The reason for such thickness was that the same layer
contained the
reaction chamber and a vent membrane above it and could not be made any
thinner. Also in
these valves, the pin has to close a concave surface over a flat one by
shrinking the former (a
geometry requiring extra pressure and creating more stress).
[028] Valves of the present invention, stretch the elastomer layer over -45
um, to close a 45 um
channel, pressing it against the concave surface of the channel (less
stressful geometry) (Figure
3b). Lower actuation pressures, more efficient closure and lower elasticity
requirements are
provided by the gasket layer, valve design of the present invention. Thinner
elastomer can be
controlled more precisely. In the example of Figure 3B, . the pin tips are
rounded to
accommodate the "cup" valve design. This cup valve design as shown, refers to
a rounded pin
which upon actuation, actuates the gasket layer and together the gasket layer
and the pin move
across the width of the fluid channel forxning a seal with the opposing first
layer, thereby
occluding the fluid channel. Alternatively, pneumatic actuation relying on a
similar principle has
been reported in all-elastomer devices exhibiting significantly lower closure
efficiency (Grover,
W. H. et*al. Sensors and Actuators B, 2003, 89, 315-323).
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[029] In an alternative embodiment, the fluid channel of the first layer
comprises a raised feature
or platform (250) which is positioned opposite the valve pin hole (20),
wherein actuation of the
pin (10,11) actuates the second gasket layer (40) to form a seal with the
platform (250), thereby
occluding the fluid channel (50). This type of valve closure is referred to as
a "gap" valve
(Figure 4).
Pins and Valve Pin Holes
[030] One of skill in the art can envision a variety of possible materials to
be used as the pins. In
one embodiment, the pins are metal wire (an example of such can be purchased
from Gambit
Corporation). One of skill in the art can envision that the smaller the pin,
the more likely it is to
act as a needle and tear or prick through an elastomer layer. Thus, when
applying the present
invention on a smaller scale, it may be preferred to use a hollow pin (e.g. a
hollow metal wire),
or any shape that is not sharp.
[031) A fluidic structure of the present disclosure comprises at least one
valve pin hole (20). In
one embodiment, each valve pin hole corresponds to one fluid channel (50).
That is, each
actuated pin corresponds to a valve pin hole whereby the actuated pin in the
valve pin hole
occludes a corresponding fluid channel.
Pin actuation
[032] The pin can be actuated (moved) by applied pressure or by coupling the
pin to a solenoid
(Electromechanisms, San Dimas, CA). The pin can be actuated pneumatically.
This can be
carried out by connecting the pin to a commercially available pneumatic
cylinder (Festo,
Hauppauge, N.Y). Applied pressure to actuate the pin as disclosed herein, can
be applied
between 0 and 45 pounds per square inch (psi).
Layer Materials
[033] The first layer (30) of the present invention can be fabricated from a
variety materials
provided the material is relatively rigid, is compatible with the reaction
reagents, is thermally
conductive, (has a low heat capacity) if the reaction to be processed requires
heating and/or
cooling. Examples of possible materials for the first layer of the present
invention, include, but
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are not limited to: DCPD (dicyclopentadiene), glass, metal (e.g. alumunim,
copper), metal coated
with a protecting layer, ceramic, polycarbonate, silicon, graphite, or DCPD
doped with any of
the above or other components known to one of skill in the art.
[034] The gasket layer (40) of the present invention can be fabricated from
several materials,
provided the gasket material is deformable (i.e. flexible, elastic), gas
permeable, is compatible
with the reaction, has enough tensile strength to withstand actuation by
mechanical pins.
Examples of possible materials for the second gasket layer of the present
invention, include, but
are not limited to: PDMS (polydimethylsiloxane), PFPE (perfluoropolyether),
ROMP (ring-
opening metathesis polymerization) polymer, various combinations of DNB
(decylnorbornene),
HNB (hexylnorbomene), and FNB (fluoronorbornene), or those polymers alone,
PTFE
(polytetrafluoroethylene), PVDF (polyvinylidene difluoride), and latex.
[035] The gasket layer-if sufficiently thick-can "absorb" a slight amount of
non-uniformity in
the hard layers. Other rigid-chip microfluidic technologies (involving only
glass or silicon)
require extremely flat surfaces at the bonding interface to get a good seal by
methods such as
anodic bonding. The gasket layer relaxes this requirement and allows the use
of manufacturing
processes such as machining and molding that may not result in ultraflat
surfaces. The gasket
thickness can be designed to make it impossible that the channels in each hard
layer be occluded,
even if substantial mechanical pressure is applied to the chip.
[036] The third layer (60) of the present invention can be fabricated from a
variety of materials,
provided the layer material is relatively rigid (can withstand force up to 80
psi), and is preferably
transparent, though transparency is not absolutely necessary. This third layer
does not have to be
compatible with the reaction given all species reaching thislayer are removed
by applied vacuum
through the vent (110). Examples of possible materials for the second gasket
layer of the present
invention, include, but are not limited to: DCPD, glass, polycarbonate, and
quartz.
Actuation of Valves
[037] The valves of the microfluidic device of the present invention require a
means of actuation.
For most efficient fluid control and leak-free operation, the valves are
actuated by mechanical
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means. That is, an object transfers force onto the second gasket layer, which
is then actuated to
occlude the fluid channel. An example of such an object is a pin. The pin can
be a hollow metal
pin (117) placed into a valve pin hole (20). The valve pin hole serves to
guide the pin to avoid
misdirection.
Assembly of Layers
[038] The layers (30, 40, 60) of the microfluidic device can be assembled
together via chemical
adhesion or mechanical means.
[039] Mechanical Assembly (Non-adhesion). Mechanical means (such as screws or
clamps)
avoid the inconsistency of multiple curing steps. Additionally, mechanical
means allow for the
apparatus to be disassembled and possibly reused. Figure 5A shows a cross
section of a gasket
chip assembled using screws, wherein two screws (270) are provided into two
screw holes (280),
wherein the two screw holes transverse the three layers thereby forming a
monolithic
microfluidic device. Alternatively, as shown in Figure SB, at least one clamp
(310) is used for
mechanically assembly of the microfluidic structure.
[040] Using mechanical assembly means, new microfluidic chip materials can be
evaluated
quickly. Mechanical assembly eliminates the considerable amount of time that
is commonly
required to develop fabrication protocols for the bonding (chemical adhesion)
of new materials.
Additionally, materials that are preferred for any desired reaction, can be
utilized and used in
conjunction with other layer materials to which they would not bond well. For
example,
commercial, ready-made materials know to be inert, such as Teflon, glass,
Chemraz, PEEK,
Simriz, Larez and others can be used despite their inability to be modified
for chemical bonding.
[041] Adhesion-less assembly also allows for the possibility of more than
three layers. For
example, one can envision a 5-layer chip with the following layers (from top
to bottom): (i)
thick, rigid valve-guiding layer; (ii) thin flexible gasket layer to act as
valve membranes; (iii)
thin, rigid layer containing flow channels; (iv) thin flexible gasket layer to
act as gas exchange
membrane; (v) thick, rigid layer containing vacuum vent channels. This
architecture has the
advantage of separating the requirements of the gasket material: the top
gasket must be tough
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and flexible but need not be gas permeable while the bottom gasket must be
permeabie but need
not be flexible or tough. This further expands the range of suitable materials
for device
fabrication.
[042] With mechanical assembly, processing methods are not limited by the need
for assembly
during partially cured states. For example, under-cured soft-gelled gasket
layers must be
supported by a substrate during handling to prevent wrinkling and damage.
Typically, in other
fabrication approaches, a thicker layer is first = stacked on the gelled layer
and bonded to it.
Adhesion-less chips allow the use of fully-cured gasket layers which have
sufficient
strength/toughness to be handled on their own (e.g. with tweezers) and lack
much of the
stickiness/tackiness often associated with undercured materials that makes
them difficult to
handle.
[043] In one embodiment, the mechanical assembly is self-aligning. When the
rigid first and
third layers are fabricated on a CNC (computer numerical control) device, the
screw holes are
placed in these layers in precise locations allowing the chip to fit together
only one possible way.
It should be noted that non-mechanical methods require manual alignment of
layers commonly
results in the mis-alignment of features, which in turn reduces the
performance of the chip and
often leads to failure.
FIGURES 5A-B
[044] The approach has been recently validated using a rigid DCPD
(dicyclopentadiene) vent
(third) layer, a rigid DCPD flow (first) layer, and a fully-cured elastic
FNB/DNB
(fluoronorbornene/decylnorbornene) gasket layer. Figure 5A shows matching sets
of 6 holes
were drilled into each of the DCPD layers-through-holes in the vent layer and
threaded holes
(280) in the flow layer. Holes were punched through the gasket layer at the 6
positions
corresponding to where the screws (270) would pass through. The three layers
of the device
were assembled and held together by screws tightened with moderate torque (by
hand). The seal
was sufficient to hold at least 45 psi of fluid pressure, tested by injecting
acetonitrile into the
flow channels. Valves in the chip functioned correctly and operated under
similar conditions as
needed to actuate valves in chips fabricated by adhesion methods.
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[045] The chip was exposed to high temperatures (100 C) for long periods of
time (2 hours)
with trapped acetonitrile (liquid and vapor) and no leaks were observed,
despite a slight
softening of the DCPD.
[046] Connections were made to the chip by inserting stainless steel tubing
into holes drilled into
the DCPD after full curing to a rigid state. Depending on the exact
size/quality of the hole and
the exact tubing diameter, a friction fit was sufficient, in several cases, to
form a liquid-tight seal
up to at least 45 psi. To ensure a superior seal, some FNB/DNB precursor was
deposited around
each piece of tubing protruding from the chip and cured in place. Other "glue"
materials may be
suitable. One could also imagine special fittings that screw into mating holes
machined into the
chip or the use of a variety of other specialized fittings. It is also
conceivable to punch holes and
insert the tubing while the DCPD or hard layers are in a "gelled" state and
cure the DCPD to
completion afterward.
[047] In one embodiment, the microfluidic structure comprising at least three
layers as described
herein, is assembled using screws (270)(Figure 5A). In an alteinative
embodiment, the
microfluidic structure comprising at least three layers as described herein,
is assembled using at
least one clarnp (310) (Figure 5B).
[048] Assembly by Adhesion. The thick layers (the first and third layer, for
example) can be
fabricated via molding as described below and shown in Figures 6-8, or by
other techniques
such as hot-embossing, injection-molding, conventional machining, etc. The
gasket layers can
similarly be fabricated by a variety of techniques such as spin coating,
casting, injection
molding, etc. Bonding methods are known in the art (see, for example, U.S.
Patent No.
7,040,338; US Application No. 11/297,651).
Molding of Layers
[049] Figures 6A-6F shows the stepwise method of forming features such as
fluid channels and
reaction area into the first layer and forming vent channels in the first
layer and providing pin
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valve holes through all three layers with the gasket layer in between the
first and third hard
layers.
[050] Some hard materials have an intermediate state in their curing profile
which resembles an
elastomer in its properties. In one embodiment, the hard layers are cast on
the corresponding
molds and cured to an intermediate (elastomer-like) state without pins and
sleeves. The gasket
layer is cast or spin-coated on a flat surface (215) such as that of a Si
wafer. The hard layers are
removed from molds (if the latter are wax molds, the wax can be washed out at
this point), and
have holes for fluid inlets and outlet (T/O) ports (25) and pin holes (20)
punched in them. Then
they are assembled with metal pins for fluid delivery and actuator pins.
Afterwards they are
joined by their bottom surfaces placing the gasket between them and cured to
their final state
resulting in a 3-layer device. This method (Figure 6A-F) assures easy pin
insertion and
adhesion of layers, which has been demonstrated sufficient to hold the chip
together throughout
the synthesis.
[051] The steps for this fabrication are as follows: vent (235) and flow (230)
layers cast on wax
molds are cured to an elastomer-like state (Figure 6A). Soft vent and flow
layers are removed
from molds, followed by hole-punching and pin insertion (Figure 6B). Thin
elastomeric gasket
layer is then cast on a flat surface and cured partially just past a gel state
(Figure 6C). The first
lower flow layer (30) is then dropped on top of the gasket layer (40). Minimal
tackiness at this
step needs to be stronger between the flow layer and the gasket layer than
between the gasket
layer and the bottom flat surface (215) (Figure 6D). After cutting off the
excess thin layer, two
layers are pulled off the casting surface (215) and inverted (Figure 6E).
After addition of the
vent layer on top of the first two, the assembly is cured to completion
resulting in a well-adhered
device comprising two hard layers (30, 60) and one soft layer (40) in between
(Figure 6F).
FIGURES 7A-7F
[052] Figures 7A, 7B. Sacrificial wax molds for both fluid (230) and vent
(235) layers. In one
embodiment, these molds are printed on Si wafers (215) by a 3-D printer. In
another embodiment
these wax molds can be made from an elastomeric "inverse mold" on a Si-wafer
or another
substrate that the wax can weakly adhere to. The bond has to be strong enough
to hold the wax
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in place, but yet weak enough to allow the wax to be released into the molded
part when the
substrate is removed. Such conditions can be optimized by one of skill in the
art.
[053] Figure 7C. The next step after preparation of the inverse mold, is to
create borders (240)
around the molds that would (a) hold the pre-polymer in a confined space and
(b) hold the I10
ports (25) in the case of fluid layer. These borders can once again be made of
an elastomer that
seals well to the substrate and does not absorb the hard pre-polymer or react
with it. The height
of these borders determines the thickness of the layers made in the next step.
The top layer
needs pin sleeves (for the valves) (20) to be attached to the mold so that
they are locked in place
when the hard polymer cures. These are attached to the wax expansions and
stand vertically, and
are held in place by a rigid "guide" (260) from above. The same connection is
made for the vent
1/0 ports. The first lower (fluid) layer connections are made through the
sides of the mold with
pins held by the elastomer border and connected to the wax expansions at the
ends of the fluid
channel features.
[054] Figure 7D. Next the assemblies of Figure 7C are filled with hard pre-
polymer, which is
allowed to cure in them (Figure 7D). In the case of the fluid layer, the pre-
polymer is covered
with a glass cover slip (300) to preserve the flat nature of the surface which
will have to be in
contact with the heating element in the final device.
[055] Figure 7E. The hard polymer is cured to the earliest gel stage that
allows unsupported
structures to hold their shape and preserve the features. Then the borders
(240), glass cover slip
(300), and the substrates (215) are removed leaving the polymer with wax and
pins (Figure 7E).
Hard layers removed from the moIds. The first (fluid) layer is depicted turned
over.
[056] Figure 7F. Spacer features (45) are placed on the fluid layer (after
turning it over) to
control the thickness of the elastomer layer (40). The elastomer pre-polymer
is poured on top of
the fluid layer with spacer features, which is immediately covered with the
top (vent) layer (60)
that rests on the supports. The entire assembly is then cured to completion
(Figure 7F).
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[057] The final step involves the removal of sacrificial wax by melting and
rinsing the chip with
organic solvents. Once the wax is removed, it yields a chip with all the
architecture necessary
for multi-step synthesis (Figure 1). It is made of materials that are inert to
chemical reactions.
The valves have thin membranes that can deflect with minimum pin pressure and
the reactor is
separated from the vacuum vent by a thin gas permeable membrane allowing
efficient
evaporations and solvent exchange.
FIGURES 8A-8D
[058] In an alternative embodiment, if the printing of the 3-D wax in the
procedures of
corresponding to Figures 6 and 7 does not yield desired smoothness of
features, the following
"tub" mold method can be used.
[059] Figure SA. Elastomer "tub" mold. Prepare elastomer molds (280) (Figure
8A) from
photoresist molds for both fluid and vent layers. The elastomer should form a
tub that will be
filled by the hard layer precursor. The height of the walls of this tub
determines the resulting
layer thickness. The fluid UO ports (25) (hollow metal pins) are inserted
through the sides of the
"tub' mold and connect to the reservoirs at the ends of fluid channels. The
reasons for making
this mold from an elastomer are (a) the ease of removal of a hard part with
dense features from a
soft mold and (b) the UO port connections will have to break the mold as the
part is removed.
[060] Figure 8B. Hard Layer Casting. Deposit catalyzed pre-polymer into the
"tub" and cover
with a glass cover slip to form a flat surface will be in contact with a
heating element in the final
device (Figure 8B).
[061] Figure SC. Gelled Hard Layer. Cure the hard polymer to a "gel" state
(just rigid enough
to be removed from the mold, but only partially cured). Remove the cover slip
and the mold and
inverted the part (Figure 8C).
[062] Figure 8D. Injection of wax into the gelled mold with an elastomer seal.
Fill the
fluidic network with the sacrificial wax by either adding melted wax onto the
surface and
removing excess with a razor blade-like tool, or by covering the mold with a
flat piece of
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elastomer sealing (290) at contact surfaces and filling the hot wax through
the UO ports (Figure
SD). Upon cooling, the wax solidifies producing the fabrication intermediates
shown in the
previous mold methods of Figures 6 and 7.
The Fluidic Structure
[063] The present disclosure comprises a first layer; a second layer
contacting said first layer,
said second layer being a flexible layer; a third layer contacting said second
layer; at least one
fluid channel, said at least one fluid channel positioned proximal to the
second layer; at least one
valve pin hole, said at least one valve pin hole passing through the third
layer and stopping at the
second layer; at least one pin, wherein the at least one pin is activatable to
actuate the second
layer, thereby occluding the at least one fluid channel; wherein the above
together forms an
integrated fluidic device.
[064] The fluidic structure of the present invention can have many
orientations. In a vertical
orientation, the first layer can a lower layer, in which case, the second
layer is a middle layer
overlying the first.layer, and the third layer is an upper layer, overlying
the second middle layer.
Alternatively, the first layer is an upper layer, wherein the second layer is
a middle layer
underlying the first layer, and the third layer is a lower layer, underlying
the second middle layer.
[065] In a horizontal orientation, the first layer is a right layer positioned
to the right of the
second layer which is positioned to the right of the third layer, which is the
left most layer.
Alternatively, the first layer is a left layer positioned to the left of the
second middle layer,
wherein the middle layer is positioned to the left of the third layer, wherein
the third layer is the
layer on the right of the middle layer.
Scale of Fluidic Structure
[066] The size and scale of the fluidic structure of the present disclosure
and the corresponding
channel and pin sizes can vary as needed for a given application. It is
apparent to one of skill in
the art that there are advantages and disadvantages at both the micron (small)
size and millimeter
(larger) size. Thus, one of skill in the art can optimize the scale of the
fluidic structure that will
work best for a given application. The fluidic structure of the present
disclosure can comprise
channels which range in size from 10 m to 1 mm in diameter having pins
ranging in size from
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0.25 inches to 12 inches or more in length and 100 m to 1 millimeter in
diameter. One can also
contemplate a pin having a diameter of 1 centimeter, and of course a pin
diameter between 1
millimeter and 1 centimeter.
Temperature Control
[067] The fluidic structure of the present disclosure can be combined with a
temperature control
device such as a heat sink (e.g. Peltier device) and a fan. A fluidic
structures can have an
attached heat sink positioned below the synthesis chip (215). An array of
temperature control
devices can be coupled with the present disclosure as needed for a particular
fluidic reaction.
One of skill in the art can provide a temperature control device to the
fluidic structure of the
present disclosure.
[068] In an alternative embodirnent a fluidic structure, and more
specifically, a synthesis chip of
the present disclosure comprising a reactor area also comprises at least one
vent channel. Such a
vent charnnel (110) (Figure 5) can be one of a variety of formations, as long
as it facilitates the
evaporation of solvent from the reactor area and enables reduction of reactor
area pressure. The
vent channel in Figure 5 forms a serpentine pattern proximal to the reactor
area. This vent
channel has an input (115) and output (120), one of which is plugged and the
other connected to
a vacuum. Another possible vent channel pattem is a right-angled U-shape
directly above the
reactor area in the second flexible layer allowing for evaporation through
this layer above the
reactor area. A vent channel is preferably in contact with the third layer and
positioned proximal
to the reactor area.
Applications
[069] Advantageous applications of the present mechanically activated fluidic
structure are
numerous. Accordingly, the present invention is not limited to any particular
application or use
thereof. In preferred aspects, the following uses and applications for the
present invention are
contemplated.
[070] In a general application, the fluidic structure is used to control fluid
flow in an integrated
fluidic device. The fluid flow in the fluid channel can be any reactant fluid.
The resulting
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process could be the synthesis of a compound. The resulting fluidic compound
could be the
result of a solvent exchange, wherein a first fluid reactant is fed through a
fluid channel, and a
solute is trapped (this application would further comprise a selective
membrane in a fluid output
channel for trapping the solute) and a subsequent second fluid reactant is fed
through the same
fluid channel, whereby the solute is suspended in the second fluid reactant.
In this way, the
fluidic structure of the present disclosure would provide a new method for
solvent exchange.
.[071] Solvent exchange capability, granted by the gas permeability of the
membrane (gasket)
coupled with the seal strength of the valves allows the device based on the
abovementioned
architecture to be used in successful multi-step synthesis of
radiopharmaceuticals such as PET
probes that could not be easily synthesized in prior devices relying on
similar synthesis
principles because they could be realized with limited material choices (Lee,
C.-C. et al. Science,
2005, 310, 1793-1797). Other microfluidic devices have been used for
radiosynthesis, but these
devices do not need to accornznodate high temperatures and pressure and thus
do not valves
(Gillies, J. M. et al. J. Appl. Rad. Isot. 2006, 64, 325-332). Although
similar valves have been
described (Yuen, P. K et al. J. Micromech. Microeng. 2000, 10, 401-409), they
would not be
applicable in such devices without the versatility of material.
[072] One could also imagine the above processes (synthesis, solvent-exchange,
purification,
etc.) being combined into an integrated fluidic process.
[073] The fluidic structure as disclosed can be used in applications
including, but not limited to:
biopolymer synthesis, cell sorting, DNA sorting, chemical synthesis,
therapeutic synthesis,
optofluidics, and semiconductor processing.
[074] In summary, a microfluidic structure and method are disclosed, where the
structure
comprises a featureless gasket layer allowing for efficient and reproducible
structure production
and assembly. Layering methods allow for the use of a variety of device
materials and easy
assembly.
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[075] While illustrative embodiments have been shown and described in the
above description,
numerous variations and alternative embodiments will occur to those skilled in
the art. Such
variations and alternative embodiments are contemplated, and can be made
without departing
from the scope of the invention as defined in the appended claims.
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