U.S. patent application number 09/739074 was filed with the patent office on 2001-08-30 for magnetically actuated fluid handling devices for microfluidic applications.
Invention is credited to Bohringer, Karl, Hatch, Anson, Kamholz, Andrew, Yager, Paul.
Application Number | 20010017158 09/739074 |
Document ID | / |
Family ID | 23843710 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010017158 |
Kind Code |
A1 |
Kamholz, Andrew ; et
al. |
August 30, 2001 |
Magnetically actuated fluid handling devices for microfluidic
applications
Abstract
Magnetically actuated fluid handling devices using magnetic
fluid to move one or more fluids (gases or liquids or both) through
microsized flow channels are provided. Fluid handling devices
include micropumps and microvalves. Magnetically actuated slugs of
magnetic fluid are moved within microchannels of a microfluidic
device to facilitate valving and/or pumping of fluids and no
separate pump is required. The magnets used to control fluid
movement can be either individual magnets moved along the flow
channels or one or more arrays of magnets whose elements can be
individually controlled to hold or move a magnetic slug. Fluid
handling devices include those having an array of electromagnets
positioned along a flow channel which are turned on and off in a
predetermined pattern to move magnetic fluid slugs in desired path
in the flow channel. The fluid handling devices of the present
invention can handle gases and liquids simultaneously and thus can
be made to be self-priming. These devices are more resistant to
fluctuations in fluid input than other types of micropumps which
need to be tuned to pump either liquid or gas. In a particular
embodiment, a micropump having a loop channel containing a
stationary magnetic slug and one or more moving slugs is
provided.
Inventors: |
Kamholz, Andrew; (Seattle,
WA) ; Hatch, Anson; (Seattle, WA) ; Bohringer,
Karl; (Seattle, WA) ; Yager, Paul; (Seattle,
WA) |
Correspondence
Address: |
GREENLEE WINNER AND SULLIVAN P C
5370 MANHATTAN CIRCLE
SUITE 201
BOULDER
CO
80303
US
|
Family ID: |
23843710 |
Appl. No.: |
09/739074 |
Filed: |
December 15, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09739074 |
Dec 15, 2000 |
|
|
|
09464379 |
Dec 15, 1999 |
|
|
|
Current U.S.
Class: |
137/251.1 ;
137/1 |
Current CPC
Class: |
B01L 2300/0816 20130101;
F16K 2099/0094 20130101; F04B 43/046 20130101; B01L 2300/088
20130101; B01L 2400/0694 20130101; F16K 13/10 20130101; B01L
2200/0673 20130101; F04F 99/00 20130101; B01L 3/502738 20130101;
B01L 2300/0861 20130101; F16K 2099/0084 20130101; F04B 43/14
20130101; B01L 3/50273 20130101; F16K 99/0046 20130101; Y10T
137/2191 20150401; B01L 3/502784 20130101; F16K 99/0019 20130101;
F04B 17/044 20130101; F16K 31/08 20130101; Y10T 137/0318 20150401;
Y10T 137/4643 20150401; B01L 2400/043 20130101 |
Class at
Publication: |
137/251.1 ;
137/1 |
International
Class: |
G05D 007/00 |
Claims
We claim:
1. A fluid handling device comprising: at least one microsized flow
channel in fluid communication with at least one fluid inlet and at
least one fluid outlet; and one or more slugs of magnetic fluid
located within the flow channel, wherein a slug can be held
stationary or moved in the channel by at least one magnet and
wherein a slug blocks fluid flows through the channel when it is
stationary and a slug pulls or pushes fluid through the channel
when it is moved.
2. The fluid handling device of claim 1, further comprising at
least one slug inlet in fluid communication with the flow channel
for conducting the slug into the flow channel.
3. The fluid handling device of claim 2, wherein the slug inlet
comprises a flow channel containing at least one vent.
4. The fluid handling device of claim 1, further comprising at
least one slug outlet in fluid communication with the flow channel
for conducting the slug out of the flow channel.
5. The fluid handling device of claim 2, further comprising at
least one slug outlet in fluid communication with the flow channel
for conducting the slug out of the flow channel.
6. The fluid handling device of claim 1, wherein an array of
magnets is used to move one or more slugs through the flow
channel.
7. The fluid handling device of claim 6 wherein the array of
magnets is an array of electromagnets.
8. The fluid handling device of claim 1 wherein the magnetic fluid
is a ferrofluid.
9. The fluid handling device of claim 1 for use with liquid
fluids.
10. The fluid handling device of claim 1 for use with aqueous
media.
11. The fluid handling device of claim 1 for use with fluids that
are gases.
12. A method for moving fluid in a microsized flow channel
comprising the steps of: providing at least one microsized flow
channel in fluid communication with at least one fluid inlet and at
least one fluid outlet; providing one or more slugs of magnetic
fluid located within the flow channel, a slug being under the
magnetic control of at least one magnet; and using at least one
magnet to move a slug through the flow channel causing a net flow
of fluid into the fluid inlet and a net outflow of fluid out of the
fluid outlet.
13. A fluid handling device comprising: at least one microsized
flow channel forming a loop, the flow channel being in fluid
communication with at least a first fluid inlet and at least a last
fluid outlet; at least a first and second slug of magnetic fluid;
both located within the flow channel; at least one magnet arranged
and adapted so as to control said first slug to move within said
flow channel; wherein, the volume of said first slug is less than
the volume between a most closely-spaced fluid inlet and outlet of
said device; at least one magnet arranged and adapted so as to
control said second slug in a stationary position between the first
fluid inlet and the last fluid outlet; wherein, the volume of the
stationary slug is less than the volume between the first fluid
inlet and the last fluid outlet on either side of the slug.
14. The fluid-handling device of claim 13 comprising: at least two
sets of fluid inlets and outlets; and at least a third slug of
magnetic fluid under control of a magnet arranged and adapted so as
to control said third slug to move within said flow channel.
15. The fluid handling device of claim 13 wherein the loop is
circular.
16. The fluid handling device of claim 13 wherein the magnets are
permanent magnets and at least one of the magnets is mechanically
moveable to follow the path of the loop.
17. The fluid handling device of claim 15 having one stationary
slug and two moving slugs.
18. A microfluidic device comprising a fluid handling device of
claim 1.
19. A microfluidic device comprising a plurality of fluid handling
devices of claim 1.
20. A microfluidic device comprising a fluid handling devices of
claim 13.
21. A microfluidic device comprising a plurality of fluid-handling
devices of claim 13.
22. A microfluidic device comprising at least two of the fluid
handling devices of claim 17 wherein: the fluid inlets of the fluid
handling devices are in fluid communication with each other by
means other than the microsized flow channel; and/or the fluid
outlets of the fluid handling devices are in fluid communication
with each other by means other than the microsized flow channel;
and the magnets which move the slugs around the flow channel loops
can be operated such that when the moving slug in the first device
is merged with the stationary slug of that device, the moving slug
of at least one other device is not merged with the stationary slug
of that device.
23. A method for moving a fluid in a microfluidic device comprising
the steps of: providing in the microfluidic device a microsized
flow channel forming a loop, the flow channel being in fluid
communication with one or more fluid inlets and outlets wherein
there is at least one first fluid inlet and at least one last fluid
outlet; forming at least two slugs of a magnetic fluid material
located within the flow channel; using at least one magnet to hold
at least one slug stationary between the first fluid inlet and the
last fluid outlet so that fluid in the loop cannot flow from the
last fluid outlet to the first fluid inlet; and using at least one
magnet to move at least one slug around the flow channel loop,
thereby causing a net inflow of fluid into the fluid inlet and a
net outflow of fluid out of the fluid outlet.
24. The microfluidic device of claim 23 comprising a plurality of
slugs of magnetic gel located within the flow channel, capable of
changing shape under magnetic control to induce fluid flow within
said channel.
25. A microfluidic fluid handling device comprising: at least one
microsized flow channel in fluid communuation with at least one
fluid inlet and at least one fluid outlet; and at least one slug of
magnetic gel located within the flow channel whose shape can be
controlled by at least one magnet to block the flow of fluid in
said microchannel or to allow fluid flow within said microchannel.
Description
CROSS REFERENCED TO RELATED APPLICATIONS
[0001] This application is a continuation in-part of co-pending
application Ser. No. 09/464,379 filed Dec. 15, 1999, which is
incorporated herein by reference to the extent not inconsistent
herewith.
BACKGROUND OF THE INVENTION
[0002] This invention relates generally to fluid handling devices,
specifically to magnetically actuated devices employing slugs made
of a magnetic fluid to control fluid movement through microsized
flow channels.
[0003] Miniature fluid handling devices to control fluid movement,
which include micropumps and microvalves for use in microfluidic
devices, can be constructed using fabrication techniques adapted
from those applied to integrated circuits. Microfluidic devices
have environmental, biomedical, medical, biotechnical, printing,
analytical instrumentation, and miniature cooling applications.
[0004] Several different kinds of micropumps exist that can control
flow on the order of microliters per minute (S. Shoji and M. Esashi
(1994), "Microflow Devices and Systems", J. Micromech. and
Microeng.4:157-171). Micropumps with moving parts include
peristaltic pumps and reciprocating pumps. These reciprocating
pumps have a pressure chamber with a diaphragm driven by an
actuator and passive check valves. Passive micropumps with no
moving parts include electrohydrodynamic, electroosmotic, and
ultrasonic pumps. U.S. Pat. No. 5,876,187 describes methods of
making micromachined pumps.
[0005] Electroosmotic pumps, which rely on the use of chargeable
surfaces within the pump, are generally applied to fluid handling
in microsized systems (D. J. Harrison et al. (1992), "Capillary
Electrophoresis and Sample Injection Systems Integrated on a Planar
Glass Chip", Analytical Chemistry, 64 (17):1926-1932). Chargeable
surfaces have a fixed charge on their surface when in contact with
an appropriate fluid. Electroosmotic pumping also requires the
presence of counterions in the fluid adjacent the charged surface.
Appropriate application of an electric field to a channel having a
chargeable surface causes flow of the counterions of the fluid in
the channel and as a result flow of the fluid as a whole to effect
pumping in the channel. However, the pumping rate is dependent upon
the pH, ionic strength and ion concentration of the fluid.
Electroosmotic pumping may not be useful for applications where
these fluid properties change or where they are unknown.
[0006] U.S. Pat. Nos. 4,967,831 and 5,005,639, both issued to
Leland, disclose magnetically actuated macrosized piston pumps that
in one embodiment use a magnetically confined ferrofluid slug as a
self-sealing and self-repairing pump piston. The pumps were
described for use in heat pipes. There is no description of the use
of these pumps in microfluidic systems. The pumps described employ
permanent ring magnets and electromagnets surrounding a conduit,
but this configuration cannot readily be adapted to
microconduits.
[0007] Ferrofluid slugs have recently been used as seals in
microfabricated valves and as pistons in microfabricated pumps (H.
Hartshorne et al., "Development of Microfabricated Valves for
.mu.TAS", MicroTAS Conference Proceedings, Banff, Alberta, Canada,
October 1998, pp. 379-381; H. Hartshorne et al., "Integrated
Microfabricated Ferrofluidic Valves and Pumps for .mu.TAS", poster
presented at DARPA Conference, Dec. 3, 1998, San Diego, Calif.; H.
Hartshorne et al., "Microfabricated Ferrofluidic Valves and Pumps",
poster presented at DARPA Conference, Jul. 31, 1999, Pittsburgh,
Pa.). The references report valving of gases and liquids and
pumping of gases, but not liquids. The pump design described has a
ferrofluid piston moving in a side channel separate from the flow
channel containing the fluid inlet and outlet. Therefore, this
piston is unable to also act as a valve in the main flow channel
where the inlet and outlet are located.
[0008] Ferrofluids have been used in the design of magnetic
pipettes (Greivell, N. E. and Hannaford, B. (1997), "The Design of
a Ferrofluid Magnetic Pipette," IEEE Transactions on Biomedical
Engineering 44(3):129-135).
[0009] Macroscale pumps have been attempted using ferrofluids as
described in C. W. Miller (1974), "Magnetic Fluids: Magnetic Forces
and Pumping Mechanisms," Ph.D. Thesis, Cornell University, however
such pumps require special coatings and seals not required by the
present invention.
SUMMARY OF THE INVENTION
[0010] The present invention is generally directed to magnetically
actuated fluid handling devices employing slugs made of a magnetic
fluid to move a fluid through microsized flow channels. These fluid
handling devices include micropumps and microvalves.
[0011] In a first embodiment, this invention provides a fluid
handling device having at least one microsized flow channel in
fluid communication with at least one fluid inlet and at least one
fluid outlet. At least one slug of magnetic fluid is located within
the flow channel and can be held stationary by a magnet to block
fluid flow through the flow channel. The slug can also be moved by
a magnet to pull or push fluid through the flow channel.
[0012] In other embodiments of this invention, the device described
above can incorporate additional features to allow a variety of
fluid handling operations. For example, a fluid handling device can
incorporate one or more inlets and outlets for magnetic fluid slugs
to enter and leave the flow channel. A slug inlet can be connected
to a source of magnetic fluid to allow two or more slugs separated
by fluid to be generated. A slug outlet allows a slug to be pulled
out of the way of the fluid behind it. One or more air vents may
also be incorporated into these devices to facilitate separation of
slugs from a reservoir of magnetic fluid with air and to alternate
different fluids in the flow channel.
[0013] One primary advantage of the fluid handling devices
described herein over other micropumps is that the magnetically
actuated slug moves within the flow channels of the microfluidic
device to facilitate valving and/or pumping of fluid and no
separate pump is required.
[0014] In another embodiment, this invention provides a fluid
handling device having at least one microsized flow channel forming
a loop. The flow channel is in fluid communication with at least
one fluid inlet and at least one fluid outlet, including a first
fluid inlet and a last fluid outlet which are adjacent, yet
separated by a channel volume, from each other along the fluid
channel loop. The device also has at least two slugs of magnetic
fluid, both located within the flow channel loop. At least one slug
is moved around the flow channel loop by a magnet to pull and push
fluid from fluid inlets towards fluid outlets of the flow channel
loop. The slug is moved in the loop passing the first inlet, any
intermediate outlets and inlets, past the last outlet, and through
the channel volume separating the last outlet from the first inlet.
At least one slug is held stationary by another magnet between the
last fluid outlet and the first fluid inlet to block fluid flow
through the flow channel loop back into the first fluid inlet. The
moving slug of magnetic fluid merges with and passes through the
stationary plug of magnetic fluid as it moves around the fluid
channel loop. The combined action of the slugs in the channel has
the net effect of pumping fluid from the fluid inlets and to the
fluid outlets and particularly from the first fluid inlet to the
last fluid outlet. The volume of the stationary slug is preferably
less than the channel volume between the last fluid outlet and the
first fluid inlet, except when the stationary slug is merged with
the moving slug. The volume of the moving slug is preferably less
than the channel volume between the most closely spaced fluid inlet
and outlet in the channel loop, so that adjacent inlets and outlets
along the loop channel are not both blocked by the moving slug.
Also, if two or more sets of fluid inlets and outlets are present,
at least two moving slugs are used.
[0015] One embodiment of this invention takes advantage of the
shape-changing capabilities of magnetic gels, which are also
magnetic fluids as defined herein, to form valves and pumps. Such
magnetic gels are described, e.g. in Szabo, D. et al. (1998),
"Shape Transition of Magnetic Field Sensitive Polymer Gels,"
Macromolecules 31:6541-6548.
[0016] In all the embodiments of this invention, the magnets for
holding or moving the magnetic slug(s) may be located on one side
or both sides of the flow channel assembly, rather than surrounding
the flow channels, simplifying assembly of the microfluidic device.
In addition, the magnets used to control the magnetic fluid slug
movement can be either individual magnets moved along the flow
channels in a flow channel assembly or an array of magnets mapping
the flow channel assembly whose elements can be individually
controlled to hold or move a magnetic slug. For example, using an
array of electromagnets, magnets positioned along a flow channel
can sequentially be turned on and off to create the same effect as
a magnet moving along the flow channel. Alternatively, magnetic
fields can be generated at selected points within the flow
channel.
[0017] Methods for using the fluid handling devices of this
invention as well as microfluidic devices employing one or more
fluid handling devices of the present invention are also provided.
These microfluidic devices may combine the fluid handling devices
of the present invention with microfluidic devices already
described in U.S. Pat. Nos. 5,922,210 (Tangential Flow Planar
Microfabricated Fluid Filter and Method of Using Thereof),
5,716,852 (Microfabricated Diffusion-Based Chemical Sensor),
5,972,710 (Microfabricated Diffusion-Based Chemical Sensor),
5,948,684 (Simultaneous Analyte Determination and Reference
Balancing in Reference T-Sensor Devices), U.S. patent application
Ser. Nos. 09/346,852 (Microfabricated Differential Extraction
Device and Method), 08/823,747 (Device and Method for 3-Dimensional
Alignments of Particles in Microfabricated Flow Channels),
08/938,093 (Multiple Analyte Diffusion-Based Chemical Sensor), U.S.
Pat. No. 6,007,775 (Multiple Analyte Diffusion Based Chemical
Sensor) (Separation and Chemical Reaction), 5,948,684 (Simultaneous
Analyte Determination and Reference Balancing in Reference T-Sensor
Devices), U.S. patent application Ser. No. 09/080,691 (Liquid
Cartridge Analysis), and U.S. Pat. No. 5,971,158
(Absorption-Enhanced Differential Extraction Device).
[0018] The fluid handling devices of the present invention can
handle gases and liquids simultaneously. Therefore, these fluid
handling devices can be made self priming. In addition, these
devices are more resistant to nonuniformities in fluid input than
other types of micropumps which need to be tuned to pump either
liquid or gas. For example, in reciprocating pumps employing a
piezoelectric actuator, the piezoelectric material is set to
resonate at a given frequency which depends upon the
compressibility of the medium being pumped.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1A is a top plan diagram of a magnetically actuated
fluid handling device showing a magnetic fluid slug blocking fluid
flow into a flow channel. FIG. 1B is a top plan diagram of a fluid
handling device showing a magnetic fluid slug pulling fluid from an
inlet into a flow channel.
[0020] FIGS. 2A and 2B are top plan diagrams of a second fluid
handling device illustrating two stages in using a magnetic fluid
slug to push fluid through a flow channel.
[0021] FIGS. 3A, 3B, and 3C are top plan diagrams of a third fluid
handling device illustrating three stages in using a magnetic fluid
slug to pull fluid through a flow channel.
[0022] FIGS. 4A, 4B, and 4C are top plan diagrams of a fourth fluid
handling device illustrating three stages in using two magnetic
fluid slugs together to push and pull fluid through a flow
channel.
[0023] FIGS. 5A, 5B, and 5C are top plan diagrams of a fifth fluid
handling device illustrating three stages in using two of the fluid
handling devices shown in FIGS. 4A, 4B, and 4C to dispense
controlled amounts of a sample and an indicator fluid to a T-sensor
structure.
[0024] FIG. 6A schematically shows a set of individually
addressable permanent magnets which can be used to control movement
of magnetic fluid slugs in a fluid handling device. A separate
plate contains the magnets which can be individually moved using
linear translation drives. FIG. 6B schematically shows a
programmable permanent magnet array which can be used to control
movement of magnetic fluid slugs in a fluid handling device. A
separate plate contains an array of individually addressable
solenoids containing permanent magnets which can be individually
moved in and out of proximity to a fluid handling device. FIG. 6C
schematically shows a programmable electromagnetic array which can
be used to control movement of slugs of a magnetic fluid material
in a fluid handling device. A separate plate contains an array of
individually addressable electromagnets which can be individually
turned on or off.
[0025] FIGS. 7A, 7B, and 7C are top plan diagrams of a sixth fluid
handling device which uses a buffer fluid to isolate the sample
fluid from the magnetic fluid slug, illustrating three stages in
using a slug to push the fluids along a flow channel.
[0026] FIGS. 8A and 8B are top plan diagrams of a seventh fluid
handling device illustrating two stages in using two magnetic fluid
slugs to pull, then push fluid along a flow channel.
[0027] FIGS. 9A, 9B, 9C, and 9D are top plan diagrams illustrating
four stages in using three magnetic fluid slugs to mix two fluids
together.
[0028] FIG. 10 is a top plan diagram of a magnetically actuated
fluid handling device with a circular flow channel loop, one moving
slug, and one stationary slug, showing another aspect of the
present invention (not to scale).
[0029] FIG. 11 shows a top plan diagram of a second fluid handling
device with a circular flow channel loop, showing a device with two
inlets and outlets.
[0030] FIG. 12 shows a top plan diagram of a microfluidic device
with a plurality of loop pumps. The exemplified device combines
four separate loop pumps in parallel on a single substrate.
[0031] FIG. 13 shows a top plan diagram of a microfluidic device of
FIG. 12 with exemplary channel restrictions to improve fluidic
distribution in the device.
[0032] FIG. 14A shows a top plan view of a microchannel containing
a ferrogel valve of this invention in the closed position. FIG. 14B
shows the valve in open position.
[0033] FIG. 15 shows a top plan view of a microchannel containing a
perstaltic pump element of this invention using a ferrogel.
DESCRIPTION OF INVENTION
[0034] This invention is further described by reference to the
drawings, where the same numbers are used to identify like
features. The description of FIGS. 1A and 1B is used to describe
basic elements of the invention which are common to several of its
embodiments.
[0035] FIG. 1A is a schematic top plan diagram of a simple
magnetically actuated fluid handling device. In FIG. 1A, a single
microsized flow channel 10 is present. A flow channel is a conduit
through which it is possible for fluid to flow if the conduit is
not blocked. A microsized channel cross-section has at least one
dimension, depth or width, less than 1 mm. This definition
incorporates cross-section dimensions of 0.1 micron to 500 micron
that have been termed mesoscale in U.S. Pat. No. 5,955,029.
[0036] The flow channel is in fluid communication with at least one
fluid inlet 12 and at least one fluid outlet 14. If two parts of
the device are in fluid communication with each other it is
possible for fluid to flow from one part of the device to the other
unless the flow path is blocked. The fluid to be handled in the
device may be either a liquid or a gas. The inlet and outlet are
generally defined with respect to the direction of fluid flow, with
fluid flowing from the inlet to the outlet. The fluid inlet 12 is
defined such that the net flow of fluid through the inlet is into
the flow channel or zero if the flow channel is blocked. Similarly,
the fluid outlet 14 is defined such that the net flow of fluid
through the outlet is out of the flow channel or zero if the flow
channel is blocked. The inlet and outlet can be openings or
channels which connect to reservoirs, other channels, or other
microfluidic device elements. In a given device, an inlet may
become an outlet and an outlet may become an inlet when the
direction of fluid flow is changed, for example by changing the
direction of motion of a magnetic fluid slug.
[0037] A slug 20 of magnetic fluid 56 is shown within the pump flow
channel. A slug of magnetic fluid has sufficient volume to seal off
a portion of a flow channel in a microfluidic device to the flow of
fluid. A slug is a quantity of magnetic fluid that can be
cohesively moved or held in a microchannel of a microfluidic device
by application of a magnetic field. The quantity of magnetic fluid
in a slug for a given application depends upon the application, the
size of the channel, the path that it must traverse in the channel
(e.g., around comers, etc.), the type of fluid to be pumped, the
pressure and flow rate of fluid. The preferred material for the
slug is a magnetic fluid, which consists of a suspension of
magnetic particles in a liquid or semisolid carrier whose movement
within a micro sized flow channel can be controlled by the
application of a magnetic field. The magnetic fluid is resistant to
agglomeration and sedimentation.
[0038] The magnetic particles in the magnetic fluid are
sufficiently small so they do not interfere with the ability of the
material to seal off a portion of the flow channel or the ability
of the material to move through straight channels, curved channels
or around comers in channels. The quantity and composition of the
magnetic particles in the magnetic fluid are selected so that the
slug material is capable of responding to the application of a
magnetic field.
[0039] The carrier is selected so that it is immiscible with and
does not react with the fluid(s) to be moved through the device.
The carrier is also preferably selected so that it wets the flow
channel with equal or greater wettability than the fluid(s) to be
moved through the device. The viscosity of the carrier is
preferably selected so that the resistance to flow of the magnetic
fluid in the channel can be overcome by the applied magnetic field.
These desirable carrier properties are maintained under the
temperature, pressure and pH conditions required for a particular
application. The response of the slug material also depends upon
the magnetic strength of the magnet, the distance the magnet is
placed from the device, and the viscosities of the carrier and type
of fluid(s) to be moved through the device.
[0040] The fluid handling devices of this invention can be adapted
for use with liquids or gases or both. Liquids that can be pumped,
directed and/or valved, including both aqueous (water and aqueous
solutions) and non-aqueous liquids. Non-aqueous solutions can be
polar or non-polar liquids. Gases include oxygen, carbon dioxide,
nitrogen and gas mixtures including air. Liquids may include those
that are acidic or basic. Liquids to be pumped may include those
that are themselves suspensions of particles or emulsions
containing multiple phases. Liquids may also include gels or
creams, as long as their viscosity is sufficiently low to allow the
liquid to be pushed or pulled through the desired flow channels.
Magnetic fluid and flow channel and device components are selected
for compatibility with the liquid or gas to be pumped.
[0041] Two slugs of magnetic fluid may "pass through" each other in
a microchannel. For example, a moving slug may pass through a slug
held stationary. It will be appreciated that in such "passing
through" two slugs merge and then separate as the moving magnet
passes the stationary magnet. During merging of slugs, the magnetic
fluid therein is intermingled. Magnetic fluid slugs in a given
microfluidic device may be the same size or volume or may be
different sizes or volumes.
[0042] The preferred material for the slug 20 is a ferrofluid,
which is a stable colloidal suspension of magnetic particles in a
carrier liquid. The particles, which have an average size of about
100 Angstroms, are coated with a surfactant to prevent the
particles from sticking together, so that simple Brownian motion is
sufficient to keep them apart. A variety of different ferrofluid
compositions have been described. For example, ferrofluid
compositions are described in U.S. Pat. Nos. 5,879,580; 5,851,416;
5,667,716; and 5,656,196, and Dubois, E, (1999) "Structural Analogy
Between Aqueous and Oily Magnetic Fluids," J. Chem. Phys.
111(15):7147-7160.
[0043] Ferrofluids are available commercially from Ferrofluidics
Corporation, Nashua NH. One preferred ferrofluid composition for
use with aqueous fluids is a proprietary product from the
Ferrofluidics AGG E series which contains 1.4% by volume magnetite,
7-14% by volume oil-soluble dispersant, 80-91% by volume
water-immiscible carrier liquid, and 1-2% by volume aromatic
amine.
[0044] A magnet 30 provides a means for holding the slug 20 in
place or moving the slug through a flow channel. The term magnet is
most generally used, herein, to describe any source of a magnetic
field. The magnet can be a permanent magnet or an electromagnet.
The magnet can be located on a separate plate, fabricated on a chip
(Liakopoulos, T. M, Zhang, W., and Ahn (1995), C. H.,
"Micromachined Thick Permanent Magnet Arrays on Silicon Wafers",
IEEE Trans. on Magnetics, 32(5):5154-5156) or placed within a
microchannel. To hold or move a slug through the flow channel, one
or more magnets can be operated to be held or moved along the flow
channel using one or more two-dimensional translation mechanisms,
or an array of magnets can be used. For example, a magnet array can
include a set of permanent magnets mounted on an array of
solenoids. The solenoids are addressable individually and can move
the individual permanent magnets toward and away from the flow
channels, thereby effectively "switching on and off" localized
magnetic fields that drive the slug. A magnet array can also
include a set of electromagnets spaced periodically throughout the
region the piston travels. The timing of operation can be
electronically controlled, with the electromagnets turning on and
off in sequence such that the slug is appropriately held or moved
through the microchannel. In some cases, a magnet used to hold a
slug stationary in a flow channel can be eliminated by redesigning
part of the flow channel so that the magnetic fluid slug has a very
high flow resistance in that area. For example, if a section of the
flow channel were made narrow enough, the magnetic fluid slug could
remain stationary in that section due to its high flow resistance.
Programmed selective switching on and off of magnets in an array
can be used to select paths for fluid flow through a microfluidic
device having multiple fluid flow paths by appropriate valving with
slugs held stationary and fluid pumping using moving slugs.
[0045] The fluid handling device shown in FIG. 1A can be used to
block fluid flow from the inlet 12 through the flow channel 10. A
magnet 30 is used to bring the slug 20 up to the fluid inlet and
hold it there.
[0046] The fluid handling device shown in FIGS. 1A and 1B can also
be used as a simple fluid transport device to move fluid from one
point to another. FIG. 1A shows the starting position of the slug
20, while FIG. 1B shows the slug pulling fluid 45 behind it as the
magnet 30 moves the slug towards the fluid outlet 14. As the slug
passes through the outlet, it pulls fluid through the outlet as
well. Once fluid has been pulled into the channel, the direction of
slug motion can be reversed, so that the slug can push fluid
through the channel as well as pull it.
[0047] FIGS. 2A and 2B show a simple fluid handling device where a
slug 20 is used to push fluid 45 in the flow channel 10 toward the
fluid outlet 14. FIG. 2A shows the starting position of the slug
20, which is held in position with the magnet 30. The fluid inlet
12 is shown connected to inlet channel 11 through which fluid is
injected. FIG. 2B shows the slug pushing fluid in the channel
toward the fluid outlet. The magnet 30 is used to move the slug
towards the fluid outlet. Rather than being injected into flow
channel 10, fluid can also be allowed to enter the flow channel
from the inlet by capillary action. In this case, a valve (which
can be another slug) can be positioned in the flow channel on one
side of the fluid inlet 12 and closed once the slug is moved to the
other side of the fluid inlet 12. This valve can be placed in the
flow channel 10 or in the inlet channel 11, for example, and is
used to limit the amount of fluid 45 being moved.
[0048] FIGS. 3A, 3B, and 3C show a fluid handling device which
additionally contains a slug inlet 62 for conducting a slug 20 of
magnetic fluid 56 into the flow channel 10, the slug inlet being in
fluid communication with the flow channel. The slug inlet can
include inlet channels 75, which may be connected to reservoirs
(shown schematically as 70) of slug material, and can also include
tubes, syringes, and like devices which can inject slug material.
In FIG. 3A, the slug inlet is shown as slug inlet channel 57
connected to a slug reservoir 70. The slug inlet may contain a
valve to limit fluid flow into the inlet or the closed end of a
reservoir, tube or syringe may serve to limit fluid flow into the
inlet. In FIG. 3A, the magnetic fluid present in the reservoir and
inlet channel acts as a valve restricting fluid flow into the slug
inlet. Also shown in FIGS. 3A, 3B, and 3C is a fluid reservoir
(shown schematically as 40) in fluid communication with the fluid
inlet. The slug and fluid reservoirs can have any shape which
allows introduction and/or removal of fluids from the reservoirs.
If capillary action or injection partially fills the flow channel
10 with fluid before a slug 20 is conducted into the flow channel,
the slug can also be used to push the fluid in front of it along
the flow channel.
[0049] FIGS. 3A, 3B, and 3C, respectively, show a sequence of steps
in which a slug 20 is formed and used to pull fluid from the fluid
reservoir 40 and out the fluid outlet 14. In FIG. 3A, a magnet 30a
is used to pull magnetic fluid 56 out of the slug reservoir 70 and
into the slug inlet channel 57. In FIG. 3B, magnetic fluid 56 is
pulled into the flow channel 10 when magnet 30a is switched off (or
moved away) and another magnet 30b is brought near the slug inlet
62 to draw magnetic fluid in the flow channel 10. In FIG. 3C,
magnet 30b is used to move the magnetic fluid slug in the channel
towards outlet 14, forming a magnetic fluid slug 20 that separates
from the slug reservoir and pulls fluid 45 from the fluid reservoir
into the flow channel.
[0050] FIGS. 4A, 4B, and 4C show a fluid handling device similar to
that shown in FIGS. 3A, 3B, and 3C, except that it additionally
contains a vent 68 in the slug inlet channel (e.g., a valved inlet
for introduction of a second fluid, e.g., a gas, such as air). This
vent contains a valve 69 which allows the vent to be opened and
closed. The position of the vent can be moved or additional vents
can be added to achieve various types and combinations of fluid
handling as would be readily apparent to one skilled in the art.
The vent in FIGS. 4A-C is illustrated as an air vent to allow
introduction of air into the flow channel. The vent may be
connected to another fluid reservoir, e.g., a reservoir of air,
nitrogen, inert gas or the like or a reservoir of liquid, e.g.,
oil, hydrocarbon, water or other liquid.
[0051] FIGS. 4A, 4B, and 4C, respectively, illustrate a sequence of
steps in which two slugs 20a and 20b are formed in the flow channel
10, used together to push and pull fluid from the fluid reservoir
through the flow channel and dispense a controlled amount of fluid
through the outlet. In FIG. 4A, the vent is closed and the first
slug is pulled into the flow channel and moved partway along the
channel, pulling fluid behind it as described for FIG. 3C. FIG. 4B
shows the vent being opened and a second slug 20b being pulled into
the flow channel by a magnet. Because the vent is open, the second
slug 20b is separated from the magnetic fluid in the slug inlet
channel by a gap containing the fluid entering via the vent (e.g.,
air). FIG. 4C shows that as the magnet pulls the second slug 20b
along the channel, it pushes fluid ahead of it and pulls vent fluid
21 into the inlet and flow channel behind it.
[0052] FIGS. 5A, 5B, and 5C illustrate a sequence of steps in which
two of the fluid handling devices shown in FIG. 4A can be used
together to dispense controlled amounts of a sample and an
indicator fluid to a T-sensor structure 101 as described in U.S.
Pat. No. 5,948,684. FIG. 5A shows two magnetic fluid slug pairs 20a
and 20b drawing up sample and indicator fluid (45 and 145,
respectively). FIG. 5B shows the fluids approaching the central
channel 107 of the T-sensor structure. FIG. 5C shows the fluids in
the central channel 107 of T-sensor structure 101, where diffusion
of the fluids occurs.
[0053] FIGS. 6A, 6B, and 6C show three different ways,
respectively, of providing magnets to move the magnetic fluid slugs
in a fluid handling device. For convenience, the fluid handling
device shown is that in FIG. 5A. In these figures, the magnets 30
are located on in an array on a plate or substrate 55 separate from
the fluid handling device. The array of magnets is sufficiently
large to allow interaction with magnetic fluid in any flow channel
(or combination of flow channels) in the device. The array of
magnets thus will be selected and positioned to map the flow
channels in the device (or at least to map those flow channels in
which valving or pumping by magnetic slugs is desired). FIG. 6A
shows a set of individually addressable permanent magnets 30 which
can be individually moved along set paths 59 using linear
translation drives (not shown). FIG. 6B shows an array 58 of
individually addressable solenoids containing permanent magnets.
The magnets of the array can be moved up and down to move them
closer to or farther away from the channels 10 of the device (FIG.
5A). FIG. 6C shows an array of individually addressable
electromagnets 67. The magnets of the array can be independently
turned on to generate a magnetic field or off away from the
channels 10 of the device (FIG. 5A). The magnet arrays of FIGS.
6A-6C can be programmed to move in a given pattern with time, to
move up and/or down in a given pattern with time or to turn on and
off in a given pattern with time to accomplish a desired valving or
fluid handling application. The magnet arrays can be uniform grids
with uniform spacing between magnets or the array can be
constructed with magnets positioned and spaced so that the magnets
therein align with flow channels or align with desired fluid paths
in the device.
[0054] FIGS. 7A, 7B, and 7C illustrate a sequence of steps,
respectively, by which a fluid handling device slightly different
from that shown in FIG. 4A can be used to dispense controlled
amounts of sample fluid 45 isolated from the magnetic fluid 56 by a
buffer fluid 105. The use of a buffer fluid limits any
contamination of the sample fluid by the magnetic fluid. In FIG.
7A, buffer fluid 105 is injected into the flow channel 10 through a
buffer fluid inlet 102. In FIG. 7B, sample fluid 45 is injected
into the flow channel through a sample fluid inlet 12. In FIG. 7C,
a slug 20 is pulled into the flow channel as described previously
for FIG. 4B. By controlling the distance the slug 20 travels in the
flow channel 10, the amount of sample fluid dispensed can also be
controlled.
[0055] FIGS. 8A and 8B show a fluid handling device which
additionally contains a slug outlet 64 for conducting a slug out of
the flow channel, the slug outlet being in fluid communication with
the flow channel. The slug outlet can include outlet channels,
which may be connected to magnetic fluid collection reservoir 60.
In FIG. 8A, the slug outlet is shown as an outlet channel 110
connected to a magnetic fluid collection reservoir 60. The slug
outlet can contain a valve to limit fluid flow into the outlet or
the closed end of a reservoir can limit fluid flow into the outlet.
In FIG. 8B, a magnetic fluid slug 20a is moved into the outlet to
act as a valve.
[0056] FIGS. 8A and 8B illustrate another way that two magnetic
fluid slugs 20 can be used to push and pull fluid through the flow
channel 10 and through an outlet 14. FIG. 8A shows two magnetic
slugs 20a and 20b moving fluid along the channel as previously
described for FIG. 4C. As shown in FIG. 8B, when the first slug 20a
reaches the outlet channel 110, a magnet is used to move it into
the outlet channel 110 and hold it there, thus creating a valve
blocking fluid flow into that channel. The second slug 20b can then
push fluid ahead of it along the flow channel and through the
outlet 14. More than two slugs can be used to pump greater
quantities of fluid from the reservoir. In this case, each slug is
inserted into the flow channel and moved along the channel and out
the outlet, thereby pushing fluid ahead of it towards the fluid
outlet. The magnetic slugs are collected in magnetic fluid
collection reservoir 60 and may be recycled for use. The ability to
divert the slug in front of the fluid can simplify fluid delivery
to the next stage of a microfluidic device.
[0057] FIGS. 9A through 9D illustrate how three magnetic fluid
slugs 20a , 20b and 20c can be used to mix two fluids at an
microchannel intersection. The magnets are not shown. In FIG. 9A,
two fluids, first fluid 52 and second fluid 53 have been drawn into
a T intersection of a channel (initial fluid separation indicated
by line 54) where diffusion between them will begin to occur. In
FIGS. 9B-9D, the directions of slug movement are changed to mix the
liquids and achieve faster diffusion between the two liquids.
[0058] The basic fluid handling devices described above can also be
combined for use in microfluidic circuits incorporating H-Filters,
micromixers, microcytometers and many other microfluidic
components, as will be apparent to those skilled in the art. Other
microfluidic applications for which such fluid handling devices can
be useful are cell patterning, which requires controlled input flow
rates (Kenis, P.J., Ismagilov, R. F., and Whitesides, G. M. (1999),
Science, 285:83-85), separation of particles by dielectrophoresis,
which requires pressure driven flow (Yang, J. et al. (1999),
Analytical Chemistry, 71:911-918), and flow injection analysis,
which requires very fast controlled flow (Hodder, P. S.,
Blankenstein, G. and, Ruzicka, J.(1997), Analyst, 122:883-887,
Bokenkamp, R.et al. (1998), Analytical Chemistry,70:232-236).
[0059] FIG. 10 shows a top plan diagram of a magnetically actuated
micropump with a flow channel which forms a loop. In this diagram,
the loop-forming flow channel 90 is circular, although the flow
channel is not limited to a circular shape. The flow channel is in
fluid communication with a fluid inlet 12, and a fluid outlet 14,
both depicted as channels connected to inlet and outlet reservoirs
37 and 35, respectively. The fluid inlet is defined such that the
net flow of fluid through the inlet over one pump cycle is into the
pump. Similarly, the fluid outlet is defined such that the net flow
of fluid through the outlet over one pump cycle is out of the
pump.
[0060] FIG. 10 shows two slugs of magnetic fluid, a moving slug 20m
and a stationary slug 20s both located within the flow channel 90.
The pump contains a first inlet 12 and a last outlet 14 separated
by a channel volume 29. The moving magnetic fluid slug in FIG. 10
is moved around the flow channel loop by a moving magnet 30m. The
volume of the moving slug preferably is less than the volume 29 of
the flow channel between the first fluid inlet and last outlet and
is preferably the same as that of the stationary slug. The magnetic
slug 20m may be moved by a variety of known mechanical and
electronic techniques. The stationary slug in FIG. 10 20s is held
stationary between the first fluid inlet and the last fluid outlet
using a stationary magnet 30s. In this embodiment, the volume of
the stationary slug should be less than volume 29 between the first
fluid inlet and last outlet on either side of the stationary slug,
except when the two slugs are merged.
[0061] The pump shown in FIG. 10 operates as follows. As the moving
slug 20s is moved clockwise through the flow channel 90 between the
inlet 12 and the outlet 14, it forces fluid in through the inlet
and out through the outlet. As the moving slug approaches the
stationary slug, it pushes all the fluid ahead of it out through
the outlet before it merges with the stationary slug. While the two
slugs are merged, no pumping action occurs. The two slugs remain
merged until a magnet provides a field sufficient to pinch off a
new movable slug 20m from the merged slugs. When a mechanically or
electrically (clockwise) rotating permanent magnet 30m controls the
position of the moving slug, the moving slug emerges from the
merged slug when the rotating magnet passes the inlet. Once the
moving slug moves past the inlet, the pumping cycle repeats
itself.
[0062] Because the pumping rate may not be constant over time, a
single pump is most useful for applications that are not affected
by pulsatility. For example, an application may require a uniform
flow rate only over a short period of time. If that time period is
less than the time period over which the pump produces a uniform
flow rate, the application is not affected by the pump pulsatility.
If a rotating permanent magnet controls the position of the moving
slug, the pump pulsatility can be reduced by increasing the
rotation speed of the magnet while the moving slug is merged with
the stationary slug. Similarly, if a magnet array controls the
position of the moving slug, the pump pulsatility can be reduced by
increasing the rate of switching between magnet array elements
mapping the flow channel while the moving slug is merged with the
stationary slug.
[0063] FIG. 11 shows a pump design which uses one stationary slug
20s and two moving slugs 20m. Loop micropumps such as this with
more than one set of inlets and outlets can be used to produce a
more constant pumping rate. The loop pump has two inlets and two
outlets including a first inlet 12a and a last outlet 14b. Both
outlets 14a and 14b are connected to outlet reservoir 35 and both
inlets 12a and 12b are connected to inlet reservoir 37. In FIG. 11,
one moving slug 20m is at the bottom of the flow channel and the
other is merged with the stationary slug (20m+ 20s) at the top of
the flow channel. The arrows show the direction of fluid flow. It
is evident that for this design, fluid flows through the pump even
when the stationary slug is merged with one moving slug, because of
the pumping action of the second moving slug 20m. Therefore, pump
pulsatility is reduced. If more than one set of inlets or outlets
are present in the design, there should be at least one stationary
slug and at least two moving slugs.
[0064] The amount of magnetic fluid used for each stationary slug
is limited by the requirement that the stationary slug be small
enough not to block its adjacent pump inlet and outlet (the first
inlet and the last outlet) except when it is merged with a moving
slug. The amount of magnetic fluid used for each moving slug is
preferably small enough so that the slug does not block the most
closely-spaced pump inlet and outlet which does not contain a
stationary slug between the inlet and outlet. Preferably, both
moving and stationary slugs have the same volume, with one
stationary slug being placed between the most closely-spaced inlet
and outlet and having the same volume as the volume of the flow
channel between that inlet and outlet. There may be one or more
stationary slugs in a loop flow channel. If individual permanent
magnets rather than magnet arrays are used to control slug
positions, additional permanent magnets are required when
additional slugs are used.
[0065] In addition, averaging the output of multiple pumps with
loop-forming flow channels can be used to obtain a more constant
pumping rate over time. FIG. 12 illustrates such a microfluidic
device which combines four separate loop pumps in parallel
connected to an inlet reservoir 37 and an outlet reservoir 35. The
inlet reservoir is in fluid communication with a main reservoir or
other fluid source 41 and the outlet reservoir is in fluid
communication with a device 42 to which the fluid is to be
delivered. Alternatively, a loop pump or multiple loop pump
configuration can be used to pump fluid from a device to a fluid
exit, fluid waste stream or like conduit. The pumps are similar to
those shown in FIG. 10 and are labeled A through D. For simplicity,
the magnets are not shown; however, the direction of motion of the
moving slugs is indicated by arrows. In FIG. 12, the pump timing is
adjusted so that the position of the moving slug in each pump is
ninety degrees ahead of the position of the moving slug in the pump
above it (e.g., the position of the moving slug in pump B is ninety
degrees ahead of that in pump A). With this configuration, only one
pump at a time is in the inactive part of the cycle where the
moving and stationary slugs are merged. In FIG. 12, pump D is shown
in the inactive part of the cycle. The relative positions of the
individual pumps in the device of FIG. 12 are not critical. The
relative timing of slug passage in the loops is, however, important
to achieve a more constant pumping rate. The offset between the
positions of the moving slugs can be selected to be compatible with
the volume of the moving slugs and the channel volumes between the
last outlets and the first inlets. It may be beneficial in a
multiple loop pump device like that of FIG. 12 to adjust the
relative sizes of inlet and outlet channels, the sizes of the
reservoirs or the positioning of channels communicating with the
fluid source or device to optimize fluidic distribution in the
device and to minimize backwards pumping in the device.
[0066] An exemplary microfluidic device of FIG. 12 with channel
restrictions to improve fluid distribution in the device is shown
in FIG. 13 which illustrates channel restrictions 75-77 in the
inlet reservoir and channel restrictions 78-80 in the outlet
reservoir. The relative widths of the channel restrictions, which
are positioned in the inlet and outlet reservoirs between adjacent
inlets and outlets, respectively, are selected to improve pump
efficiency in the directions indicated by arrows and to minimize
backward pumping and any displacement of stationary plugs. In the
specific embodiment shown, the restrictions increase in width in
the order 75<76<77 and 78<79<80. Further, restriction
78 (in the outlet reservoir) is smaller in width than restriction
77 (in the inlet reservoir).
[0067] The multiple loop pump devices of FIGS. 12 and 13 can be
implemented on a single substrate. Multiple loop pumps can also be
combined in parallel by stacking them in a multilayer device as
described in U.S. patent application Ser. No. 09/080,691 (Liquid
Analysis Cartridge) which is incorporated by reference herein to
the extent not inconsistent herewith.
[0068] FIGS. 14A and 14B depict a microfluidic valve formed in a
microchannel 10 with a slug of magnetic fluid 20 made of a
ferrogel. When magnets 30 are activated creating a magnetic field
32, as shown in FIG. 14A, the ferrogel responds by deforming to
fill the microchannel 10 and block flow of liquid (indicated by the
arrow) in the microchannel. When magnets 30 are inactive, the
ferrogel 20 flattens, as shown in FIG. 14B, leaving space within
the microchannel 10 for fluid to flow.
[0069] FIG. 15 shows a peristaltic pump using successive slugs of
ferrogel 20. When the first set of magnets 30 are activated, the
ferrogel fills microchannel 10, temporarily blocking fluid flow and
squeezing fluid forward to the next set of magnets, 30a , which are
off, allowing fluid flow through the microchannel, to the third set
of magnets 30b which are activated, temporarily blocking fluid
flow. Pulsing activation of the magnets causes peristaltic flow of
the fluid within the channel.
[0070] The fluid handling devices described above can include a
substrate or base member and a cover plate, not shown, which closes
the channel. Preferably the base is a plastic material or silicon,
although other similar materials could be used, such as glass,
fused silica, crystalline quartz, fused quartz, and polysilicon.
Preferably, the cover is plastic for a plastic base or glass for a
silicon base, although similar materials could be used as already
described for the base.
[0071] The flow channels are preferably formed in the planar
surface of a plastic substrate using laser cutting and lamination.
However, other means known to the art such as microinjection
molding can also be used. The flow channels are preferably formed
in the planar surface of a silicon substrate using standard
photolithographic procedures followed by wet chemical etching.
However, other micromachining processes may be used, such as LACE,
LIGA, reactive ion etching, and sputter etching.
[0072] The depth of the flow channels is preferably between about
20 microns and about 1 mm. The width of the channels is preferably
no greater than about 1 mm, and preferably between 100 and 400
microns. The dimensions of the device are chosen such that laminar
flow is maintained and that the Reynolds number is preferably less
than or equal to about 1. The channel dimensions are also selected
so that the flow resistance in the channel can be overcome with the
magnets selected. With a silicon base, wet chemical etching of the
base results in a trapezoidal channel geometry. The angles of the
channel walls with respect to the top surface of the base vary
around the channel due to the etching differences for different
crystal planes. With a plastic base, laser cutting and lamination
would produce a rectangular channel geometry. The surface of the
flow channels in the base and the lower surface of the cover plate
can be treated with an oxygen plasma or using other processes to
adjust the surface energy of the channel and modify its wettability
by the fluid and the slug material (Flounders, A. W., Brandon, D.
L., and Bates, A. H (1997), "Patterning of Immobilized Antibody
Layers via Photolithography and Oxygen Plasma Exposure", Biosens.
Bioelecton. 12:(6):447-456 and Ratner, B. D. (1995), "Surface
Modification of Polymers: Chemical, Biological and Surface
Analytical Challenges", Biosens. Bioelecton. 10,
(9-10):797-804).
[0073] The preferred embodiments described above illustrate rather
than limit the invention. As will be understood by those skilled in
the art, various materials, processes and parameters can be varied
to achieve the objectives of this invention to provide microsized
fluid handling devices. This invention is limited only by the scope
of the claims appended thereto.
[0074] All references cited herein are incorporated by reference
herein to the extent not inconsistent with the disclosure
herein.
* * * * *