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BACKGROUND OF THE INVENTION
Microfabricated devices are used in a wide variety of industries, ranging
from the integrated circuits and microprocessors of the electronics
industry to, in more recent applications, microfluidic devices and systems
used in the pharmaceutical, chemical and biotechnology industries.
Because of the extreme small scale of these devices, as well as the highly
precise nature of the operations which they perform, the manufacturing of
these microfabricated devices requires extremely high levels of precision
in all aspects of fabrication, in order to accurately and reliably produce
the various microscale features of the devices.
In a number of these disciplines, the manufacturing of these
microfabricated devices requires the layering or laminating of two or more
layers of substrates, in order to produce the ultimate device. For
example, in microfluidic devices, the microfluidic elements of the device
are typically produced by etching or otherwise fabricating features into
the surface of a first substrate. A second substrate is then laminated or
bonded to the surface of the first to seal these features and provide the
fluidic elements of the device, e.g., the fluid passages, chambers and the
like.
While a number of bonding techniques are routinely utilized in mating or
laminating multiple substrates together, these methods all suffer from a
number of deficiencies. For example, silica-based substrates are often
bonded together using thermal bonding techniques. However, in these
thermal bonding methods, substrate yields can often be extremely low, as a
result of uneven mating or inadequate contact between the substrate layers
prior to the thermal bonding process. Similarly, in bonding semi malleable
substrates, variations in the contact between substrate layers, e.g.,
resulting from uneven application of pressure to the substrates, may
adversely affect the dimensions of the features within the interior
portion of the device, e.g., flattening channels of a microfluidic device,
as well as their integrity.
Due to the cost of substrate material, and the more precise requirements
for microfabricated devices generally, and microfluidic devices,
specifically, it would generally be desirable to provide an improved
method of manufacturing such devices to achieve improved product yields,
and enhanced manufacturing precision. The present invention meets these
and a variety of other needs.
SUMMARY OF THE INVENTION
The present invention is generally directed to improved methods of
manufacturing microfabricated devices, and particularly, microfluidic
devices. In particular, in a first aspect, the present invention provides
methods and apparatuses for bonding microfabricated substrates together.
In accordance with the methods of the present invention, a first substrate
is provided which has at least a first planar surface, a second surface
opposite the planar surface, and a plurality of apertures disposed through
the first substrate from the first surface to the second surface. A vacuum
is applied to the apertures, while the first planar surface of the first
substrate is mated with a first planar surface of the second substrate.
The mating of these substrates is carried out under conditions wherein the
first surface of the first substrate is bonded to the first surface of the
second substrate. Such conditions can include, e.g., heating the
substrates, or applying an adhesive to one of the planar surfaces of the
first or second substrate.
In a related aspect, the present invention also provides an apparatus for
manufacturing microfluidic devices in accordance with the methods
described above. Specifically, such apparatus typically comprises a
platform surface for holding a first substrate, the first substrate having
at least a first planar surface and a plurality of holes disposed
therethrough, and wherein the platform surface comprises a vacuum port
connected to a vacuum source, for applying a vacuum to the plurality of
holes. The apparatus also comprises a bonding system for bonding the first
surface of the first substrate to a first surface of a second substrate.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 illustrates the layered fabrication of a typical microfluidic
device, from at least two separate substrates, which substrates are mated
together to define the microfluidic elements of the device.
FIG. 2 illustrates a mounting table and vacuum chuck for bonding substrates
together according to the methods of the present invention.
FIG. 3 illustrates an apparatus for mounting and thermally bonding
substrates together.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is generally directed to improved methods of
manufacturing microfabricated substrates, and particularly, to improved
methods of bonding together microfabricated substrates in the manufacture
of microfluidic devices. These improved methods of bonding substrates are
generally applicable to a number of microfabrication processes, and are
particularly well suited to the manufacture of microfluidic devices.
As used herein, the term "microscale" or "microfabricated" generally refers
to structural elements or features of a device which have at least one
fabricated dimension in the range of from about 0.1 .mu.m to about 500
.mu.m. Thus, a device referred to as being microfabricated or microscale
will include at least one structural element or feature having such a
dimension. When used to describe a fluidic element, such as a passage,
chamber or conduit, the terms "microscale," "microfabricated" or
"microfluidic" generally refer to one or more fluid passages, chambers or
conduits which have at least one internal cross-sectional dimension, e.g.,
depth, width, length, diameter, etc., that is less than 500 .mu.m, and
typically between about 0.1 .mu.m and about 500 .mu.m. In the devices of
the present invention, the microscale channels or chambers 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 prepared in accordance with the present invention
typically include at least one microscale channel, usually at least two
intersecting microscale channels, and often, three or more intersecting
channels disposed within a single body structure. Channel intersections
may exist in a number of formats, including cross intersections, "T"
intersections, or any number of other structures whereby two channels are
in fluid communication.
The body structure of the microfluidic devices described herein typically
comprises an aggregation of two or more separate layers 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.
FIG. 1 illustrates a two layer body structure 10, for a microfluidic
device. In preferred aspects, the bottom portion of the device 12
comprises a solid substrate that is substantially planar in structure, and
which has at least one substantially flat upper surface 14. A variety of
substrate materials may be employed as the bottom portion. Typically,
because the devices are microfabricated, substrate materials will 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, and particularly in those applications where electric fields are
to be applied to the device or its contents.
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 polymeric substrates are readily manufactured using available
microfabrication techniques, as described above, or 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 (See U.S. Pat. No. 5,512,131). 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 bottom substrate or portion 12,
as microscale grooves or indentations 16, using the above described
microfabrication techniques. The top portion or substrate 18 also
comprises a first planar surface 20, and a second surface 22 opposite the
first planar surface 20. In the microfluidic devices prepared in
accordance with the methods described herein, the top portion also
includes a plurality of apertures, holes or ports 24 disposed
therethrough, e.g., from the first planar surface 20 to the second surface
22 opposite the first planar surface.
The first planar surface 20 of the top substrate 18 is then mated, e.g.,
placed into contact with, and bonded to the planar surface 14 of the
bottom substrate 12, covering and sealing the grooves and/or indentations
16 in the surface of the bottom substrate, to form the channels and/or
chambers (i.e., the interior portion) of the device at the interface of
these two components. The holes 24 in the top portion of the device are
oriented such that they are in communication with at least one of the
channels and/or chambers formed in the interior portion of the device from
the grooves or indentations in the bottom substrate. In the completed
device, these holes function as reservoirs for facilitating fluid or
material introduction into the channels or chambers of the interior
portion of the device, as well as providing ports at which electrodes may
be placed into contact with fluids within the device, allowing application
of electric fields along the channels of the device to control and direct
fluid transport within the device.
Conditions under which substrates may be bonded together are generally
widely understood, and such bonding of substrates is generally carried out
by any of a number of methods, which may vary depending upon the nature of
the substrate materials used. For example, thermal bonding of substrates
may be applied to a number of substrate materials, including, e.g., glass
or silica based substrates, as well as polymer based substrates. Such
thermal bonding typically comprises mating together the substrates that
are to be bonded, under conditions of elevated temperature and, in some
cases, application of external pressure. The precise temperatures and
pressures will generally vary depending upon the nature of the substrate
materials used.
For example, for silica-based substrate materials, i.e., glass
(borosilicate glass, Pyrex.TM., soda lime glass, etc.), quartz, and the
like, thermal bonding of substrates is typically carried out at
temperatures ranging from about 500.degree. C. to about 1400.degree. C.,
and preferably, from about 500.degree. C. to about 1200.degree. C. For
example, soda lime glass is typically bonded at temperatures around
550.degree. C., whereas borosilicate glass typically is thermally bonded
at or near 800.degree. C. Quartz substrates, on the other hand, are
typically thermally bonded at temperatures at or near 1200.degree. C.
These bonding temperatures are typically achieved by placing the
substrates to be bonded into high temperature annealing ovens. These ovens
are generally commercially available from, e.g., Fischer Scientific, Inc.,
and LabLine, Inc.
Polymeric substrates that are thermally bonded, on the other hand, will
typically utilize lower temperatures and/or pressures than silica-based
substrates, in order to prevent excessive melting of the substrates and/or
distortion, e.g., flattening of the interior portion of the device, i.e.,
channels or chambers. Generally, such elevated temperatures for bonding
polymeric substrates will vary from about 80.degree. C. to about
200.degree. C., depending upon the polymeric material used, and will
preferably be between about 90.degree. C. and 150.degree. C. Because of
the significantly reduced temperatures required for bonding polymeric
substrates, such bonding may typically be carried out without the need for
high temperature ovens, as used in the bonding of silica-based substrates.
This allows incorporation of a heat source within a single integrated
bonding system, as described in greater detail below.
Adhesives may also be used to bond substrates together according to well
known methods, which typically comprise applying a layer of adhesive
between the substrates that are to be bonded and pressing them together
until the adhesive sets. A variety of adhesives may be used in accordance
with these methods, including, e.g., UV curable adhesives, that are
commercially available. Alternative methods may also be used to bond
substrates together in accordance with the present invention, including
e.g., acoustic or ultrasonic welding and/or solvent welding of polymeric
parts.
Typically, a number of microfabricated devices will be manufactured at a
time. For example, polymeric substrates may be stamped or molded in large
separable sheets which can be mated and bonded together. Individual
devices or bonded substrates may then be separated from the larger sheet.
Similarly, for silica-based substrates, individual devices can be
fabricated from larger substrate wafers or plates, allowing higher
throughput of the manufacturing process. Specifically, a number of channel
structures can be manufactured into a first substrate wafer or plate which
is then overlaid with a second substrate wafer or plate. The resulting
multiple devices are then segmented from the larger substrates using known
methods, such as sawing (See, e.g., U.S. Pat. No. 4,016,855 to Mimata,
incorporated herein by reference), scribing and breaking (See Published
PCT Application No. WO 95/33846), and the like.
As noted above, the top or second substrate is overlaid upon the bottom or
first substrate to seal the various channels and chambers. In carrying out
the bonding process according to the methods of the present invention, the
mating of the first and second substrates is carried out using vacuum to
maintain the two substrate surfaces in optimal contact. In particular, the
bottom substrate may be maintained in optimal contact with the top
substrate by mating the planar surface of the bottom substrate with the
planar surface of the top substrate, and applying a vacuum through the
holes that are disposed through the top substrate. Typically, application
of a vacuum to the holes in the top substrate is carried out by placing
the top substrate on a vacuum chuck, which typically comprises a mounting
table or surface, having an integrated vacuum source. In the case of
silica-based substrates, the mated substrates are subjected to elevated
temperatures, e.g., in the range of from about 100.degree. C. to about
200.degree. C., in order to create an initial bond, so that the mated
substrates may then be transferred to the annealing oven, without any
shifting relative to each other.
One example of an apparatus for use in accordance with the methods
described herein is shown in FIG. 2. As shown, the apparatus includes a
mounting table 30, which comprises a platform surface 32, having a vacuum
port 34 disposed therethrough. In operation, the top substrate, e.g.,
having the plurality of holes disposed therethrough, is placed upon the
platform surface and maintained in contact with that surface by virtue of
the application of a vacuum through vacuum port 34. Although FIG. 2 shows
the platform surface as being the upper surface of the mounting table, it
will be appreciated that such a device would also function in an inverted
orientation, relying upon the applied vacuum to maintain the substrate in
contact with the platform surface. The platform may also comprise one or
more alignment structures for maintaining the substrate in a set,
predefined position. These alignment structures may take a variety of
forms, including, e.g., alignment pins 36, alignment ridges, walls, or
wells disposed upon the mounting surface, whereupon placement of the
substrates in accordance with such structures ensures alignment of the
substrates in the appropriate position, e.g., over the vacuum port, as
well as aligning the individual substrate portions with other substrate
portions, as described in greater detail below. In addition to such
structures, alignment may also be facilitated by providing the platform at
an appropriate angle, such that gravity will maintain the substrate in
contact with the alignment structures. Vacuum port 34 is disposed through
the platform surface and mounting table, and is connected via a vacuum
line 38 to a vacuum source (not shown), e.g., a vacuum pump.
The first substrate is placed upon the platform surface such that the
planar surface of the top substrate faces away from the platform surface
of the mounting table, and such that the holes in the substrate are in
communication with the vacuum port in the platform surface of the mounting
table. Alignment of the holes over the vacuum port is typically
accomplished through the incorporation of alignment structure or
structures upon the mounting table platform surface, as described above.
In order to apply vacuum simultaneously at a plurality of the holes in the
top substrate, a series of vacuum ports may be provided through the
platform surface. Preferably, however, the platform surface comprises a
series of grooves 40 fabricated therein, and extending outward from a
single vacuum port, such that each of the plurality of holes in the top
substrate will be in communication with the vacuum port via at least one
of these grooves or "vacuum passages," when the top substrate is placed
upon the platform surface.
The bottom substrate, also having a first planar surface, is then placed on
the top substrate such that the first planar surface of the bottom
substrate mates with that of the top substrate. Again, the alignment
structures present upon the platform surface will typically operate to
align the bottom substrate with the top substrate as well as maintain the
substrates over the vacuum port(s). The alignment of the various substrate
portions relative to each other is particularly important in the
manufacture of microfluidic devices, wherein each substrate portion may
include microfabricated elements which must be in fluid communication with
other microfabricated elements on another substrate portion.
A vacuum is then applied through the vacuum passages on the platform
surface, and to the holes through the top substrate. This acts to pull the
two substrates together by evacuating the air between their planar
surfaces. This method is particularly useful where the top and bottom
substrates are elements of microfluidic devices, as described above.
Specifically, upon mating the top substrate with the bottom substrate, the
holes disposed through the top substrate will generally be in
communication with the intersecting channel structures fabricated into the
planar surface of the bottom substrate. In these methods, the channel
networks enhance the efficiency of the bonding process. For example, these
channel networks typically cover large areas of the surface of the bottom
substrate, or the space between the two substrates. As such, they can
enhance the efficiency with which air is evacuated from this space between
the two substrates, ensuring sufficient contact between the substrates
over most of the planar surfaces of the two substrates for bonding. This
is particularly the case for those areas between the substrates that are
immediately adjacent the channel structures, where complete bonding is
more critical, in order to properly seal these channels.
In addition to more efficiently removing air from between the substrates,
the application of vacuum at each of the plurality of holes in the top
substrate, as well as through the intersecting channel structures between
the two substrates results in a more even application of the pressure
forcing the substrates together. Specifically, unevenly applied pressures
in bonding methods can have substantial adverse effects on the bonding
process. For example, uneven application of pressures on the two
substrates during the bonding process can result in uneven contact between
the two surfaces of the two substrates, which, as described above, can
reduce the efficiency and quality, as well as the effective product yield
of the bonding process.
Further, even where substrates are completely bonded under such uneven
pressure, e.g., for thermally bonded polymeric substrates or substrates
bonded with adhesives, such uneven pressures can result in variations in
the dimensions of the internal structures of the device from one location
in a microfabricated device to another. Again, the channel networks
extending across wide areas of the interior portion of the two substrates,
e.g., fabricated into the surface of the second substrate, allows
application of vacuum across a substantially larger, and more evenly
distributed area of the substrates interior portion.
In addition to the vacuum chuck, the bonding system shown in FIG. 3 also
includes a heat source, e.g., a controllable heat source such as heat gun
42, for elevating the temperature of the substrates 12 and 18 while they
are mounted on the platform surface/mounting table 30. For bonding silica
based substrates, this heat source applies an elevated temperature to the
two substrates to create a preliminary bond between the substrates, so
that they can be readily transferred to an annealing oven without the
substrates shifting substantially relative to each other. This is
generally accomplished by heating the two substrates to between about
90.degree. C. and about 200.degree. C. In the case of polymeric
substrates, this heat source can take the place of the annealing oven by
elevating the temperature of the polymeric substrates to appropriate
bonding temperatures, e.g., between about 80.degree. C. and 200.degree. C.
Further, this can be done while the substrates are mounted upon the
mounting table, and while a vacuum is being applied to the substrates.
This has the effect of maintaining an even, constant pressure on the
substrates throughout the bonding process. Following such initial bonding,
the substrates are transferred to an annealing oven, e.g., as described
above, where they are subjected to bonding temperatures between about
500.degree. C. and 1400.degree. C., again, as described above.
Although illustrated in FIG. 3 as a heat gun, it will be readily
appreciated that the heat source portion of the apparatus may include
multiple heat sources, i.e., heat guns, or may include heating elements
integrated into the apparatus itself. For example, a thermoelectric heater
may be fabricated into or placed in thermal contact with the platform
surface/mounting table 30, which itself, may be fabricated from a
thermally conductive material. Such thermal bonding systems are equally
applicable to both polymeric substrates and silica based substrates, e.g.,
for overall bonding of polymeric substrates, or for producing the initial,
preliminary bonding of the silica-based substrates.
Alternate bonding systems for incorporation with the apparatus described
herein include, e.g., adhesive dispensing systems, for applying adhesive
layers between the two planar surfaces of the substrates. This may be done
by applying the adhesive layer prior to mating the substrates, or by
placing an amount of the adhesive at one edge of the adjoining substrates,
and allowing the wicking action of the two mated substrates to draw the
adhesive across the space between the two substrates.
In certain embodiments, the overall bonding system can include automatable
systems for placing the top and bottom substrates on the mounting surface
and aligning them for subsequent bonding. Typically, such systems include
translation systems for moving either the mounting surface or one or more
of the top and bottom substrates relative to each other. For example,
robotic systems may be used to lift, translate and place each of the top
and bottom substrates upon the mounting table, and within the alignment
structures, in turn. Following the bonding process, such systems also can
remove the finished product from the mounting surface and transfer these
mated substrates to a subsequent operation, e.g., separation operation,
annealing oven for silica-based substrates, etc., prior to placing
additional substrates thereon for bonding.
Although the present invention has been described in some detail by way of
illustration and example for purposes of clarity and understanding, it
will be apparent that certain changes and modifications may be practiced
within the scope of the appended claims. All publications, patents and
patent applications referenced herein are hereby incorporated by reference
in their entirety for all purposes as if each such publication, patent or
patent application had been individually indicated to be incorporated by
reference.
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