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Description  |
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Microfluidic systems have been previously described for carrying out a
number of operations, including, e.g., capillary electrophoresis (Manz et
al., J. Chromatog. 593:253-258 (1992)), gas chromatography (Manz et al.,
Adv. In Chromatog. 33:1-66 (1993)), cell separations (U.S. Pat. No.
5,635,358) and the like. Generally, such devices have been described in
the context of proof-of-concept experiments, where they have been used in
operations primarily performed by highly skilled technicians. Despite the
advancements made with respect to these devices, however, such devices
have not been adapted for use by less sophisticated operators.
In particular, the microfluidic devices and systems for controlling and
monitoring the devices described to date, have generally included bulky,
complex and expensive prototypical systems whose use requires complex
series of operations and or a high level of skill on the part of the
operator. Further, such systems are generally fabricated in the lab, where
time and funding can be at a premium, resulting in little or no attention
being given to features of the device that are not specifically directed
to the fluidic elements. As such, these devices tend to be extremely
sensitive to operator handling, and by implication, operator error. It
would therefor be desirable to provide microfluidic devices and/or systems
which are more "user friendly," i.e., more resistant to operator error,
and particularly, operator handling error. The present invention meets
these and other needs.
SUMMARY OF THE INVENTION
The present invention generally provides improved microfluidic devices,
apparatus and systems which reduce the potential for errors which arise
from operator mishandling of such devices. In particular, the present
invention provides microfluidic devices which comprises a substrate having
a first surface and at least one edge, at least two intersecting
microscale channels disposed in the substrate, and a detection window in
the first surface which permits transmission of an optical signal from at
least one of the at least two intersecting channels. These devices also
comprise a manual handling structure attached to the substrate for
handling the microfluidic device substantially without contacting the
first surface of the substrate. Also provided are apparatus for utilizing
these devices, which apparatus include electrical control systems for
applying an electric field across each of the at least first and second
intersecting channels within the device, as well as optical detectors
disposed adjacent to the detection window within the device for receiving
the optical signal.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 schematically illustrates an embodiment of a microfluidic device
incorporating a manual handling structure.
FIG. 2 schematically illustrates an alternate embodiment of a microfluidic
device incorporating a manual handling structure.
FIGS. 3A, 3B, and 3C schematically illustrates a further embodiment of a
microfluidic device incorporating a manual handling structure from
perspective, top, and bottom views, respectively.
FIG. 4 illustrates an ornamental design for a microfluidic device, which
also incorporates a manual handling structure.
FIG. 5 shows a voltage controller coupled to a microfluidic device.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is generally directed to improved microfluidic
devices and systems, and particularly, microfluidic devices that are
easier to handle by the operator, without damaging, contaminating or
otherwise fouling, as a result of manual contact with the device.
Specifically, the present invention provides microfluidic devices and
systems which include manual handling structures, for allowing easy
handling of the small scale devices with minimal potential for fouling as
a result of manual contact with the device. As noted above, previously,
microfluidic devices have been used mainly in "proof of concept"
applications, by highly skilled researchers for extremely low throughput
applications, e.g., single sample separations etc. Because of the nature
of this use, it has been largely unnecessary to provide microfluidic
devices with elements to reduce or prevent operator error or mishandling.
Specifically, because such devices were used by highly skilled
researchers, the chances of their becoming damaged by operator error or
mishandling were reduced. Similarly, because these devices had been used
primarily in such "proof-of-concept" research, e.g., involving low
throughput or single sample assays, they were generally considered
disposable, somewhat obviating the need for significant barriers to
mishandling and the like.
The microfluidic devices according to the present invention, on the other
hand, are generally intended to be used by the ordinary research and
development consumer, e.g., laboratory technicians, physicians in point of
care diagnostic applications, in home testing, and the like. As such, the
devices must generally be designed to withstand or prevent a certain level
of consumer mishandling. Of particular relevance is mishandling due to
excessive contact with the microfluidic device by the operator. For
example, because microfluidic devices include channels having extremely
small cross-sectional dimensions, e.g., regularly in the range of from 1
to 15 .mu.m, these devices are extremely vulnerable to fouling as a result
of dirt, dust or other particulate matter which can be deposited in the
reservoirs of the device and potentially block one or more of the channels
of the device.
Further, in addition to fouling the interior portions of these devices,
direct contact by a user with the surface of the microfluidic device can
have a number of additional adverse effects. For example, the devices of
the present invention typically include a detection window for observing
or optically detecting the results of the operation of the device, e.g.,
assay results. Often such optical detection methods rely upon highly
sensitive instruments, detectors and the like. Accordingly, any
interference resulting from the collection of dirt or oils on this
detection window can adversely effect the amount or quality of the signal
that is transmitted by the window and detected by the detector.
Similarly, collection of dirt and oils on the surface of the microfluidic
devices can provide surface locations at which moisture may condense
during the operation of the device. Such moisture and condensation can
provide an avenue for the contamination of the device, or cross
contamination among the various fluid access ports or wells of the device.
Further, and perhaps more critically, the formation of this condensation
on the surface of an microfluidic device which employs an
electrokinetic-based material transport and direction system can also lead
to electrical shorting between adjacent reservoirs/electrodes used in
these systems, e.g., as used in preferred aspects of the present
invention. Such shorting can significantly reduce and even destroy the
efficacy of these material direction and transport systems.
The problems associated with handling the microfluidic devices are
compounded by the small size of these devices. In particular, because the
microfluidic devices described herein have relatively small external
dimensions, it is substantially more difficult to handle such devices
without contacting large portions of the surface of the device. Further,
improvements in fluid direction systems, e.g., electroosmotic systems,
have permitted a substantial reduction n the size of microfluidic devices.
As these devices shrink in size, it becomes more and more difficult to
handle them, without contacting a substantial portion of their surfaces,
potentially leading to the problems described.
By providing a means of manually handling or holding the device without
contacting the surface of the device in which the reservoirs are disposed,
one can substantially reduce the probability that dirt or dust might find
its way into the reservoirs and channels of the device. Such dust and dirt
can readily foul microfluidic channels which typically include at least
one cross sectional dimension as small as 0.1 to 10 .mu.m, and typically
in the range from about 5 .mu.m to about 100 .mu.m. Further, these manual
handling structures, prevent contact by the user or operator with the
relevant surfaces of the device, and thereby significantly reduce the
probability that any surface contamination of the device will occur, which
contamination could potentially lead to shorting and/or interference with
the detection window.
As used herein, the term "microfluidic," or the term "microscale" when used
to describe a fluidic element, such as a passage, chamber or conduit,
generally refers to one or more fluid passages, chambers or conduits which
have at least one internal cross-sectional dimension, e.g., depth or
width, of between about 0.1 .mu.m and 500 .mu.m. In the devices of the
present invention, the microscale channels preferably have at least one
cross-sectional dimension between about 0.1 .mu.m and 200 .mu.m, more
preferably between about 0.1 .mu.m and 100 .mu.m, and often between about
0.1 .mu.m and 20 .mu.m. Accordingly, the microfluidic devices or systems
of the present invention typically include at least one microscale
channel, and preferably at least two intersecting microscale channels
disposed within a single body structure.
The body structure typically comprises an aggregation of separate parts,
e.g., capillaries, joints, chambers, layers, etc., which when
appropriately mated or joined together, form the microfluidic device of
the invention, e.g., containing the channels and/or chambers described
herein. Typically, the microfluidic devices described herein will comprise
a top portion, a bottom portion, and an interior portion, wherein the
interior portion substantially defines the channels and chambers of the
device. In preferred aspects, the bottom portion will comprise a solid
substrate that is substantially planar in structure, and which has at
least one substantially flat upper surface. A variety of substrate
materials may be employed as the bottom portion. Typically, because the
devices are microfabricated, substrate materials will generally be
selected based upon their compatibility with known microfabrication
techniques, e.g., photolithography, wet chemical etching, laser ablation,
air abrasion techniques, injection molding, embossing, and other
techniques. The substrate materials are also generally selected for their
compatibility with the full range of conditions to which the microfluidic
devices may be exposed, including extremes of pH, temperature, salt
concentration, and application of electric fields. Accordingly, in some
preferred aspects, the substrate material may include materials normally
associated with the semiconductor industry in which such microfabrication
techniques are regularly employed, including, e.g., silica based
substrates such as glass, quartz, silicon or polysilicon, as well as other
substrate materials, such as gallium arsenide and the like. In the case of
semiconductive materials, it will often be desirable to provide an
insulating coating or layer, e.g., silicon oxide, over the substrate
material, particularly where electric fields are to be applied.
In additional preferred aspects, the substrate materials will comprise
polymeric materials, e.g., plastics, such as polymethylmethacrylate
(PMMA), polycarbonate, polytetrafluoroethylene (TEFLON.TM.),
polyvinylchloride (PVC), polydimethylsiloxane (PDMS), polysulfone, and the
like. Such substrates are readily manufactured from microfabricated
masters, using well known molding techniques, such as injection molding,
embossing or stamping, or by polymerizing the polymeric precursor material
within the mold. Such polymeric substrate materials are preferred for
their ease of manufacture, low cost and disposability, as well as their
general inertness to most extreme reaction conditions. Again, these
polymeric materials may include treated surfaces, e.g., derivatized or
coated surfaces, to enhance their utility in the microfluidic system,
e.g., provide enhanced fluid direction, e.g., as described in U.S. patent
application Ser. No. 08/843,212 filed Apr. 14, 1997, and which is
incorporated herein by reference in its entirety for all purposes.
The channels and/or chambers of the microfluidic devices are typically
fabricated into the upper surface of the substrate, or bottom portion,
using the above described microfabrication techniques, as microscale
grooves or indentations. The lower surface of the top portion of the
microfluidic device, which top portion typically comprises a second planar
substrate, is then overlaid upon and bonded to the surface of the bottom
substrate, sealing the channels and/or chambers (the interior portion) of
the device at the interface of these two components. Bonding of the top
portion to the bottom portion may be carried out using a variety of known
methods, depending upon the nature of the substrate material. For example,
in the case of glass substrates, thermal bonding techniques may be used
which employ elevated temperatures and pressure to bond the top portion of
the device to the bottom portion. Polymeric substrates may be bonded using
similar techniques, except that the temperatures used are generally lower
to prevent excessive melting of the substrate material. Alternative
methods may also be used to bond polymeric parts of the device together,
including acoustic welding techniques, or the use of adhesives, e.g., UV
curable adhesives, and the like.
In accordance with the present invention, the microfluidic devices and/or
systems include a manual handling structure. By "manual handling
structure" is meant a structural element that is attached to or an
integral part of the microfluidic device or system, which facilitates the
manual handling of the device or system, and prevents excess contact
between the handler and the microfluidic device, per se. The holding
structures may be fabricated as an integrated portion of the microfluidic
device, e.g., as an extension of the device's body structure, or
alternatively may comprise a separately fabricated structure that is
attached to the microfluidic device, either permanently or removably. In
the latter instance, the handling structure may be fabricated as a portion
of a separate holder assembly, into which the microfluidic device is
permanently or removably inserted. In either event, the microfluidic
device is securely inserted into the holder assembly. Typically, such
holding structures will be fabricated from a polymeric materital, e.g.,
polystyrene, polypropylene, or the other polymeric materials described
herein. These materials are selected, again for their inertness to the
various reagents, temperatures or other conditions to which the overall
device might be subjected.
By reducing or preventing contact with the device, the manual handling
structures described herein, serve to prevent fouling of the device
resulting from excess handling of the device. For example, in a first
aspect, the manual handling structures prevent the deposition of debris,
e.g., dirt, dust or other detritus, on the surface of the device resulting
from manual contact with that surface. Such debris can be deposited within
the wells or reservoirs of the device, and can potentially clog or
otherwise interfere with flow within the channels of the device. This is a
particular hazard for devices which include large numbers of ports or
reservoirs, providing greater opportunity for debris to find is way into
the channel elements. These include those devices intended for the
analysis of multiple samples, which devices can include upwards of 8, 12,
16 and even 18 or more reservoirs or ports.
As noted previously, the manual handling structures, as described in terms
of the present invention, provide the most significant advantage in
microfluidic devices which utilize either or both of electrical material
direction/transport systems, and optical detection methods and systems.
In preferred aspects, the devices, methods and systems described herein,
employ electrokinetic material transport systems, and preferably,
controlled electrokinetic material transport systems. As used herein,
"electrokinetic material transport systems" include systems which
transport and direct materials within an interconnected channel and/or
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