U.S. patent application number 13/560721 was filed with the patent office on 2012-11-22 for microfluidic devices, particularly filtration devices comprising polymeric membranes, and method for their manufacture and use.
This patent application is currently assigned to Oregon State University. Invention is credited to Sundar V. Atre, Chih-Hung Chang, Goran Jovanovic, Brian Kevin Paul, Vincent Thomas Remcho, John Simonsen.
Application Number | 20120292246 13/560721 |
Document ID | / |
Family ID | 44070840 |
Filed Date | 2012-11-22 |
United States Patent
Application |
20120292246 |
Kind Code |
A1 |
Jovanovic; Goran ; et
al. |
November 22, 2012 |
MICROFLUIDIC DEVICES, PARTICULARLY FILTRATION DEVICES COMPRISING
POLYMERIC MEMBRANES, AND METHOD FOR THEIR MANUFACTURE AND USE
Abstract
The present disclosure describes devices useful for microscale
fluid purification, separation, and synthesis. Such devices
generally comprise a fluid membrane that separates two or more
fluids flowing through plural microchannels operatively associated
with the membrane. Often, the membrane is a semipermeable membrane,
such as might be used with a filtration device, such as a dialyzer.
Devices of the present invention can be combined with other
microscale devices to make systems. For example, the devices may be
coupled with one or more microchemical microfactories, one or more
micromixers, one or more microheaters, etc. Examples of devices
made according to the present invention included an oxygenator, a
dialyzer, microheat exchangers, etc.
Inventors: |
Jovanovic; Goran;
(Corvallis, OR) ; Atre; Sundar V.; (New York,
NY) ; Paul; Brian Kevin; (Corvallis, OR) ;
Simonsen; John; (Corvallis, OR) ; Remcho; Vincent
Thomas; (Corvallis, OR) ; Chang; Chih-Hung;
(Corvallis, OR) |
Assignee: |
Oregon State University
the State of Oregon acting by and through the State Board of
Higher Education on behalf of
|
Family ID: |
44070840 |
Appl. No.: |
13/560721 |
Filed: |
July 27, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13292903 |
Nov 9, 2011 |
8273245 |
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13560721 |
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13068037 |
Apr 29, 2011 |
8137554 |
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13292903 |
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11243937 |
Oct 4, 2005 |
7955504 |
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13068037 |
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60616877 |
Oct 6, 2004 |
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Current U.S.
Class: |
210/321.6 |
Current CPC
Class: |
A61M 1/16 20130101; A61M
2205/50 20130101; B01D 2313/21 20130101; A61M 1/3472 20130101; A61M
1/1698 20130101; A61M 2205/3334 20130101; B01D 71/10 20130101; B01D
71/68 20130101; B01D 2313/38 20130101; B01D 61/18 20130101; A61M
2205/3368 20130101; B01D 63/08 20130101; B01D 63/088 20130101 |
Class at
Publication: |
210/321.6 |
International
Class: |
B01D 63/00 20060101
B01D063/00 |
Claims
1. A fluid purification device, comprising: a microchannel fluidic
device comprising plural microchannels; a semipermeable fluid
membrane operatively associated with the plural microchannels; and
plural posts positioned to impinge at least a first fluid flowing
to the microchannels.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/292,903, filed Nov. 9, 2011, which is a
continuation of U.S. patent application Ser. No. 13/068,037, filed
Apr. 29, 2011, which is a continuation of U.S. patent application
Ser. No. 11/243,937, filed Oct. 4, 2005, which claims the benefit
of the earlier filing date of U.S. Provisional Application No.
60/616,877, filed on Oct. 6, 2004. The entire disclosures of these
prior applications are incorporated herein by reference.
FIELD
[0002] The present disclosure concerns microchannel devices having
polymer membranes operatively associated therewith, such as
purification devices having membranes for filtering fluids, one
example being a dialyzer.
BACKGROUND
[0003] There are a number of important systems that require fluid
purification, particularly liquid purification. Community water
systems, for example, obtain water from local sources, such as
lakes and rivers, but such water sources often contain impurities,
and also may contain bacteria and other microbiological organisms,
that can cause disease. Consequently, water from surface sources
must be purified before it can be consumed. Water treatment plants
typically clean water by taking it through the following processes:
(1) aeration; (2) coagulation; (3) sedimentation; (4) filtration;
and (5) disinfection. Portable water purification systems would
benefit the production of potable water in areas where there are
few if any water treatment plants.
[0004] Fluid oxygenators also provide an important example of fluid
purification. Oxygenator is the main element of the heart-lung
machine, which takes over the work of the lungs by adding oxygen to
and removing carbon dioxide from the blood. Inside the oxygenator,
blood is channelled along capillary membranes. The inner lumen of
the fibres is streamed with oxygen or oxygen enriched air. Oxygen
diffuses through the microporous membrane into the blood, while
carbon dioxide diffuses out of the blood into the gas stream and is
thereby removed. Most oxygenators also include a heat exchanger to
maintain the correct temperature of the patient's blood. The
oxygenated blood is channelled back to the patient.
[0005] Another important example of liquid purification is
dialysis. The chemical composition of blood must be controlled to
perform its essential functions of bringing nutrients and oxygen to
the cells of the body, and carrying waste materials away from those
cells. Blood contains particles of many different sizes and types,
including cells, proteins, dissolved ions, and organic waste
products. Some of these particles, including proteins such as
hemoglobin, are essential for the body to function properly.
Others, such as urea, a waste product from protein metabolism, must
be removed from the blood. Otherwise, they accumulate and interfere
with normal metabolic processes. Still other particles, including
many of the simple ions dissolved in the blood, are required by the
body in certain concentrations that must be tightly regulated,
especially when the intake of these chemicals varies.
[0006] The kidneys are largely responsible for maintaining the
chemistry of the blood by removing harmful particles and regulating
the blood's ionic concentrations, while keeping the essential
particles. Kidneys act like dialysis units for blood, making use of
different particle sizes and specially-maintained concentration
gradients. Blood passes through membrane-lined tubules of the
kidney, analogous to the dialysis tubes used in dialysis units.
Particles that can pass through the membrane pass out of the
tubules by diffusion, thus separating the particles that remain in
the blood from those that will be removed from the blood and
excreted.
[0007] Kidneys can effectively maintain the body's chemistry as
long as at least ten percent of their functional units are working.
Damage to the kidneys that causes the functional capacity to drop
below this level may cause fatal illness unless an artificial
system performs the work of the kidneys. Without artificial kidney
dialysis, toxic wastes build up in the blood and tissues, and
cannot be filtered out by the ailing kidneys. This condition is
known as uremia, which means literally "urine in the blood." Tens
of thousands of people currently require kidney dialysis, and the
number is growing. Kidney dialysis is intrusive, expensive, and
complicated. Patients suffer from current treatment protocols due
to extensive side effects. Home dialysis is much preferable to the
current practice of having patients treated at dialysis centers.
Improved technology is needed, however, to make home dialysis
feasible and affordable for patients.
[0008] Conventional dialysis units are configured as hollow fibers.
The membranes are manufactured using spinning technology and
generally are about 35.mu. thick. The membrane is highly porous
with the exception of the inner .about.1.mu., which actually
performs the separation, retaining blood cells but allowing small
molecules to diffuse therethrough. These known dialyzers use
membranes typically made of cellulose acetate, cuprophan or
polysulfone. Blood is pumped through these fibers, and then back
into the patient. The membrane has a molecular weight cut-off that
allows most solutes in the blood to pass out of the tubing but
retains the proteins and cells. Thus, artificial kidney dialysis
uses the same chemical principles that are used naturally in the
kidneys to maintain the chemical composition of the blood.
Diffusion across semipermeable membranes, polarity, and
concentration gradients are central to the dialysis process for
both natural and artificial kidneys.
SUMMARY
[0009] The present invention is directed to microscale fluid
purification, separation, and synthesis devices. Generally, such
devices comprise a fluid membrane that separates two or more fluids
flowing through plural microchannels operatively associated with
the membrane. The fluids can both be liquids, gases, or a liquid
and a gas, such as may be used for gas absorption into a liquid.
Often, the membrane is a semipermeable membrane, such as might be
used with a filtration device, such as a dialyzer.
[0010] Devices of the present invention can be combined with other
devices to make systems. For example, the devices may be coupled
with: one or more microchemical microfactories, such as
nanofactories useful for making, amongst other materials,
dendrimers; one or more micromixers, such as a micromixer
comprising posts positioned to impinge fluid flowing to the
microchannels or a micromixer comprising regions of hydrophobic
surface and hydrophilic surface; one or more microheaters; etc.
[0011] One example of a device made according to the present
invention is an oxygenator. For this embodiment, the fluid is a
gas, namely oxygen. For oxygenating blood, the liquid component is
blood.
[0012] Microheat exchangers also can be made using the method
described herein.
[0013] Particular materials had to be developed for use with
certain embodiments of the device disclosed herein. For example, a
new composite material was made comprising nanocrystalline
cellulose filler and a polysulfone polymeric material. The
composite can comprise any suitable amount of nanocrystalline
cellulose filler, with likely amounts ranging from greater than
zero weight percent nanocrystalline filler to about 10 percent
filler, and more likely from about 1 percent to about 5 percent
nanocrystalline filler. A dialyzer comprising the composite
membrane also is disclosed. One embodiment of the dialyzer
comprised a dialyzer membrane comprising nanocrystalline cellulose
filler and a polysulfone polymeric material, and a microchannel
fluidic device fluidly associated with the membrane to provide a
blood flow and a dialysate flow adjacent the membrane.
[0014] In order to make the nanocrystalline cellulose-polymer
composite, a new method was devised for making an organic
dispersion of nanocrystalline cellulose. The method comprised first
forming an aqueous dispersion of nanocrystalline cellulose. A
mixture was then formed comprising the aqueous dispersion and an
organic liquid having a boiling point higher than water. The water
was then selectively removed to form a second mixture comprising
the nanocrystalline cellulose and the organic liquid. Water can be
selectively removed by a process similar to distillation, such as
by heating the composite mixture to a temperature sufficient to
remove the water but not the organic liquid, reducing the pressure
sufficient to allow selective water removal, or both. A person of
ordinary skill in the art will realize that a number of organic
liquids can be used to practice this method. Solely by way of
example, and without limitation, the organic liquid may be
dimethylformamide, n-methylpyrollidone, tetrahydrofuran, or
combinations thereof.
[0015] The nanocrystalline cellulose may be prepared from a
suitable source, such as a material selected from the group
consisting of wood, cotton, Tunicin, Cladophora sp., Valonia,
bacteria, chitin, potato starch, and combinations thereof. The
nanocrystalline cellulose also may be surface modified to make it
more compatible with the polymeric material. The surface modified
cellulose may be surface modified by a physical process, such as
flame or corona discharge oxidation, or by a chemical process using
a material selected, without limitation, from the group consisting
of silyl, trimethyl silyl, epoxy, isocyanate, acetate, maleate,
sulfate, phosphate, an ester/sulfate mix, anhydrides, and
combinations thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0017] FIGS. 1A-1C provide AFM images of cellulose nanocrystals,
with the top image at 400 nm scale, middle image, a measurement
showing a typical length of 191 nm, and the bottom image showing
the lowest observed height of 3.7 nm.
[0018] FIGS. 2A and 2B schematically illustrates flow
mal-distributions that occur on a dialysate side of a conventional
fiber-type dialyzer.
[0019] FIG. 3 illustrates one embodiment of a microscale dialyzer
according to the present invention.
[0020] FIGS. 4A-4D are schematic diagrams illustrating one
embodiment of a microchannel array having a filter membrane
integrally associated therewith.
[0021] FIG. 5 is a plan view of one embodiment of a MECS dialyzer
according to the present invention.
[0022] FIG. 6 is a plan view of the blood flow side and dialysate
flow side of one embodiment of a dialyzer according to the present
invention.
[0023] FIG. 7 is a schematic drawing illustrating a multi-layered
dialyzer unit comprising multiple microchannel defining plates and
integrally associated polymeric membranes.
[0024] FIGS. 8A-8D illustrate plural different diffusion channel
design configurations.
[0025] FIGS. 9A-9E provide typical dimensions used to make the
plates illustrated in FIG. 8.
[0026] FIG. 10 is a schematic diagram illustrating one embodiment
of an overall dialzyer system according to the present
disclosure.
[0027] FIG. 11 is a schematic diagram of test device assembled to
test microchannel-based fluid filtration.
[0028] FIG. 12 is a schematic exploded view of a reactor developed
to demonstrate operation of a dialyzer as disclosed herein.
[0029] FIG. 13 illustrates different uses for MECS and micrototal
analysis systems (OAS).
[0030] FIG. 14A is a schematic, cross sectional diagram
illustrating an ultrasonic packaging technique before
ultrasonically welding with the energy directors protruding above
the PDMS layer.
[0031] FIG. 14B is a schematic, cross sectional diagram
illustrating the result of ultrasonic welding with the energy
directors melted down, bonding the top and bottom PC films,
compressing the PDMS layer and sealing the microchannels.
[0032] FIG. 15 is a photomicrograph illustrating that with
appropriate welding time and pressure the energy directors form
strong bonds and the PDMS compresses to create a conformal seal
against the polycarbonate top and bottom.
[0033] FIG. 16 is a diagram of (a) a "nanofractory" producing the
generalized structure of a dendrimer as (b) a branched architecture
and (c) a 3-D space-filling model.
[0034] FIG. 17 is a schematic perspective diagram of one embodiment
of an interdigital micromixer.
[0035] FIGS. 18A-18B are micrographs of (A) 75 .mu.m thick
laser-machined polyimide (200.times.) and (B) 15 .mu.m thick
micromolded PDMS (500.times.) membranes with 5-8 .mu.m pores on 100
.mu.m spacing.
[0036] FIG. 19 is a schematic diagram of an exemplary analytical
micromixer with a NSOM (Near-field optical microscopy) ear optical
fiber probe.
[0037] FIGS. 20A and 20B illustrate one approach to fabricating a
"nanofractory": (a) an in-line fractal design for compact
production of dendrimers (geometry based on the work of Pence) and
b) a close up of one of the vertices in the fractal device with
integrated micromixer, heater and separator.
[0038] FIGS. 21A-21B illustrate an alternative modular approach to
nanofractory development.
[0039] FIG. 22 illustrates using mechanical valves for dendron
extraction.
[0040] FIGS. 23A-23B are photomicrographs illustrating monolithic
sorbent materials produced in PDMS microchannels with sufficient
anchoring to yield a useful device for separations.
[0041] FIGS. 24A-24C are SEM images of a polymer made using the
embodiments of the device described herein.
[0042] FIG. 25 is a schematic plan view of a gas-liquid contactor
membrane.
[0043] FIG. 26 is a schematic drawing illustrating the basic
components of a heat exchanging system.
[0044] FIG. 27 is a schematic drawing illustrating one embodiment
of a method for making a contactor membrane by micromolding
techniques.
[0045] FIGS. 28-30B illustrate the results obtained by micromolding
contactors.
DETAILED DESCRIPTION
I. Polymer-Filler Composites
[0046] Adding fillers to polymeric systems, such as polysulfone
membranes, can improve the performance under certain conditions.
Smaller fillers seem to have special advantages. As the size of the
filler particles becomes small, the surface area of the filler
becomes correspondingly large. The polymer molecules next to the
surface are always modified by that surface. Thus, disruptions in
the configuration of the polymer chain can occur. This can serve to
increase the free volume of the polymer, resulting in greater
porosity and enhanced flux across the membrane. Also, shrinking
during membrane formation can create small cracks and voids next to
the filler particles, which increase permeability and thus overall
flux through the membrane. Perhaps surprisingly, this effect does
not necessarily result in reduced selectivity. Selectivity probably
will be altered in such a situation, but should still be
controllable, especially in the case of hemodialysis, where size is
the primary selection factor.
[0047] Prior to the present disclosure, high-aspect-ratio
nanoparticles apparently have not been used as fillers in
polysulfone membranes. These materials are long, thin rods that are
strong and stiff, and improve the mechanical properties of the
membrane. The long, thin rods also can be oriented in the membrane.
When oriented parallel to the membrane surface, they enhance the
stiffness of the membrane. When oriented perpendicular to the
membrane surface the nanoparticles decrease the compressibility of
the membrane. Highly compressible membranes typically show poor
permeability. The perpendicular orientation also allows for paths
of diffusion for the permeate and decreases the time required for
small molecules to pass through the membrane. This should increase
overall flux, which is highly desirable as it reduces the overall
size of the unit required. One embodiment of a disclosed membrane
was made using cellulose nanocrystals as a filler for polymeric
systems useful for making filters, including without limitation,
cellulose acetate, ceprophon or polysulfone.
A. Nanocrystalline Cellulose
[0048] Cellulose is the largest volume polymer on earth. It is
contained in virtually all plants and is produced by certain
bacteria and small sea animals. New uses are still being found for
cellulose. One of these is nanocrystalline cellulose (NCC).
Cellulose is a semicrystalline polymer, and crystalline portions of
the polymer may be liberated by acid hydrolysis. Battista, O. A.,
1975. Microcrystal Polymer Science. Microcrystal Polymer Science.
McGraw-Hill, New York, N.Y. Revol, J.-F., J. Giasson, J.-X. Guo, S.
J. Hanley, B. Harkness, R. H. Marchessault and D. G. Gray, Kennedy,
J. F., G. O. Phillips and P. A. Williams, 1993. Cellulose-Based
Chiral Nematic Structures. Ellis Horwood Limited 115-122. The size
and shape of these crystals varies with their origin.
Nanocrystalline cellulose from wood is 3 to 5 nm in width and
20-200 nm long; from Valonia, a sea plant, 20 nm in width and
100-2000 nm long; from cotton, 3-7 nm in width and 100-300 nm long;
from Tunicin, a sea animal, 10 nm in width and 500-2000 nm
long.
[0049] NCC production technology extends the current industrial
production of microcrystalline cellulose (MCC), which was developed
in the 1960's and is used for a variety of purposes, mostly in the
pharmaceutical and food industries. Almost every aspirin, or other
kind of tablet, contains MCC as the drug carrier or as a processing
aid. MCC is derived from bleached, dissolving grade wood pulp that
has been acid hydrolyzed. Battista, O. A. 1965. Colloidal
macromolecular phenomena. American Scientist. 53, 151-173. Under
moderate conditions of acid hydrolysis, the cellulose in the pulp
is degraded, but the rate at which the degree of polymerization
(DP) reduces slows after a certain fiber degradation level occurs.
The cellulose degradation proceeds slowly after this point, which
is called the level off degree of polymerization (LODP). Here the
cellulose consists of a large size distribution of particles,
mostly in the micron range. Under the influence of high shear, the
particles are further comminuted. It is possible to produce a
reasonable (20 to 30% or so, depending upon species and processing
method) yield of nanocrystals of cellulose. These are the basic
crystal units which exist in the crystalline domains of the
cellulose polymer. While there is a large distribution of sizes in
the industrial product, the standard deviation of the LODP is
relatively small, by biological standards at least. For commercial
MCC the LODP is about 230. Moorehead measured the crystallite
corresponding to a DP of 297 as 3.7 nm in width, 4.5 nm in
thickness, and an average of 150 nm in length (minimum length was
120 nm and maximum 330 nm). Moorehead, F. F. 1950. Text. Res. J.
20, 549. Microcrystalline cellulose is composed primarily of
aggregates of the LODP crystallites.
[0050] A film prepared from a nanocrystal suspension had a rough
density measurement of 1.6.+-.0.1 g/cc, about the same density as
the cellulose crystal. The density of crystalline cellulose
calculated from X-ray diffraction data is 1.566 g/cc. Films from
NCC are transparent and show birefringence, suggesting a high
degree of crystal orientation in the film, at least within domains.
The oriented nature of the crystals in the film is apparent even in
an optical microscope image.
[0051] The material properties of nanocrystals have not been
measured directly, but estimates for the strength and stiffness of
the cellulose are about 134 GPa for stiffness and 7,500 MPa for
strength (a theoretical calculation). Marks, R. E., Cell wall
mechanics of tracheids. Yale Univ. Press, New Haven, Conn. (1967).
Comparisons with other materials are shown in Table 1. The
extension to break of NCC is estimated to be only 2% [Marks].
TABLE-US-00001 TABLE 1 Comparison of mechanical properties for
various materials Material Strength, MPa Stiffness, GPa cellulose
crystal 7500 134 Aluminum 620 73 E-glass 3400 72 Steel 4100 207
Graphite 1700 250 Carbon nanotubes 120,000
Most commonly, cellulose nanocrystals are not prepared from wood,
but rather from a variety of biological sources: Tunicin, e.g.
Halocynthia roretzi, a sea animal; Cladophora sp. a green algae;
Valonia, a seaweed; bacteria; chitin; and even potato starch have
been used as raw materials for nanocrystal production.
[0052] Cellulose nanocrystals have useful reinforcing properties in
a variety of polymer systems as indicated by the following: Favier,
V. G. Canova, S. Shrivastava and J. Cavaille, Mechanical
percolation in cellulose whisker nanocomposites, Polymer
Engineering and Science, 37, 1732-1739 (1997); Chazeau, L. J. Y.
Cavaille and P. Terech, Mechanical behaviour above Tg of a
plasticised PVC reinforced with cellulose whiskers; a SANS
structural study. Polymer, 40, 5333-5344 (1999); Cellulose
nanocrystals have been investigated as fillers in siloxanes, such
as by Grunert, M. and W. Winter, Progress in the development of
cellulose reinforced nanocomposites, Polymeric materials, science
and engineering (2000). Poly(caprolactone), Morin, A. and A.
Dufresne, Nanocomposites of chitin whiskers from Riftia tubes and
poly(caprolactone), Macromolecules, 35, 2190-2199 (2002);
glycerol-plasticized starch, Angles, M. N. and A. Dufresne (2001).
Plasticized starch/tunicin whiskers nanocomposite materials. 2.
Mechanical behavior, Macromolecules. 34, 2921-2931; styrene-butyl
acrylate latex, Paillet, M. and A. Dufresne (2001). Chitin whisker
reinforced thermoplastic nanocomposites, Macromolecules, 34,
6527-6530; Grunnert, M. and W. Winter, Cellulose nanocrystal
reinforced cellulose acetate butyrate nanocomposites, Abstracts of
papers, 223.sup.rd National ACS meeting, Polymeric materials,
science and engineering. p. 240 (2002); epoxies, Ruiz, M., J.
Cavaille, A. Dufresne, J. Gerard and C. Graillat, Processing and
characterization of new thermoset nanocomposites based on cellulose
whiskers, Composite Interfaces, 7, 117-131 (2000); and
thermoplastic starch, Orts, W. J., S. H. Imam, J. Shey, G. M.
Glenn, M. K. Inglesby, M. E. Guttman and A. Nguyen, Effect of fiber
source on cellulose reinforced polymer nanocomposites, Annual
Technical Conference--Society of Plastics Engineers, 62.sup.nd,
2427-2431 (2004).
[0053] At very low nanocrystal loadings the composite reaches a
percolation threshold. This is the filler level at which the filler
particles begin to contact each other and form a three-dimensional
network. The modulus builds very rapidly from this point to
extremely high values. This percolation effect has been
well-studied in regards to electrical conductivity in filled
polymer systems. Above the percolation threshold, the shear modulus
has been observed to increase by more than three orders of
magnitude. This required nanocrystal loadings of only 6%. Favier,
V., G. Canova, S. Shrivastava and J. Cavaille. 1997. Mechanical
percolation in cellulose whisker nanocomposites. Polymer
Engineering and Science. 37, 1732-1739.
[0054] Cellulose nanocrystals have not been used extensively in the
common thermoplastics, e.g. polyethylene and polypropylene, as they
are more expensive than wood flour and not readily available, and
they are thermally sensitive at the temperatures commonly used to
extrude thermoplastics. Such composites also face the same
incompatibility problem inherent in wood-plastic composites because
the cellulose tends to agglomerate and the resulting composite is
more susceptible to moisture than the neat plastic. This may be
addressed, however, by surface modifying the polymeric
material.
[0055] The interest in nanocrystalline cellulose stems not only
from the superior properties of this material, but also from the
very high aspect ratios (length divided by width) available (in
some cases >500). High-aspect-ratio fillers provide improved
polymer-filler composite properties. In addition, they offer the
possibility of directionality in the mechanical properties of the
composite by aligning the nanocrystals in the desired direction.
Another advantage of NCC is its relative uniformity in terms of
size and shape. Carbon nanotubes are typically produced in a huge
array of diameters and lengths.
B. Making NCC/Organic Liquid Dispersions Using a Solvent Exchange
Process
[0056] New membranes need to be developed for use in filtration
devices, such as composite polymer-fiber materials. The
incorporation of NCC into polymers without aggregation has been
problematic. De Souza Lima, M. M. and R. Borsali, Rodlike cellulose
microcrystals: structure, properties, and applications,
Macromolecular Rapid Communications. 25, 771-787 (2004). For
example, the most advanced research group in the cellulose
nanocrystal area, Dr. DuFresne's group at EFPG-INPG in St. Martin
D'Heres Cedex, France, used freeze drying then ultrasonication to
suspend NCCs (referred to as cellulose whiskers) in
dimethylformamide (DMF).
[0057] The freeze drying step used in known processes can be
eliminated by embodiments of a solvent exchange process disclosed
herein. Solvent exchange works well as a process for transferring
NCC from an aqueous suspension to an organic liquid suspension. The
organic liquid suspension then can be used for subsequent processes
utilizing a polymeric material, such as a polysulfone, or
potentially a polymeric material precursor. Subsequent coagulation
provides a method for membrane formation. This is a potentially
enabling concept for a variety of polymer systems.
[0058] One embodiment of the method comprises forming an aqueous
dispersion of nanocrystalline cellulose. The nanocrystalline
cellulose can be made from a source of cellulose by treating the
cellulose with an acid, and comminuting the resulting cellulosic
material. A mixture is then formed comprising the aqueous
dispersion and an organic liquid. A suitable organic liquid for
this step can be selected by considering organic liquids in which
the NCC can be dispersed, the boiling point of the liquid (higher
than water but sufficiently low to allow efficient removal) and
other factors that would be understood by a person of ordinary
skill in the art, such as cost, availability, etc. By way of
example only, organic liquids currently deemed useful include
dimethylformamide, n-methylpyrollidone, and combinations thereof.
The water is then removed, without freeze drying, to form a second
mixture comprising the nanocrystalline cellulose and the organic
liquid. The water is selectively removed by processes similar to
distillation, such as be modifying the pressure and/or temperature
to allow selective removal of the aqueous phase.
[0059] The second mixture is added to a polymeric material or
polymeric material precursor to form a composite mixture. The
second mixture is then used as desired. Composite materials have
been formed using this technique. For example, an organic-liquid
dispersion of NCC has been added to polysulfone. The resulting
polymeric composite material was then formed into films. Filtration
membranes can be made by forming apertures in the composite
material. One method for forming such apertures comprises using a
sacrificial liquid that can be removed from the composite film
subsequent to its formation, such as by heating, leaving behind
pores to form a membrane.
C. Surface modification
[0060] Chemical compatibility is an important issue in composite
materials. NCC has the advantage of being easily modified by
chemical treatments. Several literature references describe the
surface modification of cellulose nanocrystals. See, for example,
Ladouce, (2000), who teaches using a variety of agents that react
with the cellulose hydroxyl group, primarily silylation, epoxy, and
isocyanate compounds; and Winter, who describes acetate, maleate,
sulfate, and trimethyl silyl modifications (2001). Successful MCC
surface modification without significant degradation of the
crystalline structure has been demonstrated by grafting phosphate,
an ester (pyromellitic), and an ester/sulfate mix [Kotelnikova,
(1993)]. The use of anhydrides as surface modifying agents also is
known [Trejo-O'Reilly, (1997)].
D. Thermal limits
[0061] NCC begins to oxidize in air around 130.degree. C. This
limits its usefulness and prohibits typical plastic processing in
extruders, injection molders, etc. In addition, dispersing dry NCC
in molten plastic requires intense shear that would most likely be
expensive and degrading to the final composite properties. However,
this thermal sensitivity should not be a serious impediment to
membrane applications, since they usually use coagulation from
solvent as the processing method. Biomedical applications also
usually incorporate low temperature processes.
E. Biocompatibility
[0062] Cellulose and cellulose derivatives have a long history in
the biomedical field. Cellulose acetate is an important polymer for
use in dialysis membranes (although in recent years it has been
losing market share to PSf). MCC is routinely used in
pharmaceuticals and foods (see above). The reaction of the body to
cellulose depends upon the type of cellulose, but generally is in
the range of none to a light body reaction. The use of bacterial
cellulose has been growing rapidly in recent years. Bacterial
cellulose, obtained from Acetobacter xylinium, has shown surprising
results as a wound dressing and a venture to commercialize its use
has begun. Bacterial cellulose is also showing promise as a
material for microsurgery.
[0063] Thus, while NCC has not yet been tested for
biocompatibility, prior experience with cellulose in biomedical
applications indicates that it will be biocompatible.
II. Dialysis Unit
[0064] A disclosed embodiment of a dialysis unit according to the
present invention is based on a modified-microchannel architecture
(MMA). This unit advances a new paradigm in haemotreatment. The
design is a MECS-based, mass transfer/heat transfer/chemical
reactor device for haemodialysis, haemofiltration and
haemoreaction. This unit takes advantage of convective and
diffusional motion of fluids (blood, dialysate, etc.), and
dramatically improves (reduces the time, lessens the blood cell
damage, etc.) device operation.
A. Technical Rationale
[0065] Mal-distribution of dialysate flow occurs due to uneven and
inconsistent spacing between individual fibers in a conventional
dialyzer. Areas with stagnant flow, as well as areas with developed
shunt flow, dramatically reduce the efficiency of the mass transfer
on the dialysate side. FIG. 2 schematically illustrates flow
mal-distributions that occur on a dialysate side of a conventional
fiber-type dialyzer 20. The spacing between individual fibers 22 is
generally small, thus diffusion is an important mechanism of mass
transfer in the inter-fiber space 24. The characteristic diffusion
time from a membrane surface into the bulk of dialysate can be
estimated as .lamda..sub.D=.lamda..sup.2/D [s], where .lamda. [m]
is the characteristic diffusion length (distance between the wall
of the fiber and the center of the bulk flow) and D [m.sup.2/s] is
the diffusion coefficient of the diffusing molecule.
[0066] This characteristic diffusion time has to be compared with
all other characteristic times (.tau..sub.d--the mean residence
time of dialysate, .tau..sub.b--the mean residence time of blood
flow through fibers, and .tau..sub.HD--the overall duration of
haemodialysis) pertinent to the operation of the conventional
dialysis unit. An efficient dialyzer design requires that
.tau..sub.D<<.tau..sub.d; .tau..sub.b; .tau..sub.HD.
[0067] If the characteristic inter-fiber space 24 in regions with
developed shunt flow is of the order of millimeters (10.sup.-3 m)
than the characteristic diffusion time .tau..sub.D is approximately
100 s. Previous research demonstrates that microscale devices
radically reduce the characteristic time required for mass transfer
in separation devices. Unlike the conventional dialysis unit, the
microtechnology-based design of the disclosed embodiments maintain
microscale dimensions evenly on both sides of the membrane. By
maintaining the characteristic inter-fiber space substantially
uniformly at 100 .mu.m the characteristic time .tau..sub.D is about
1 s.
[0068] To optimize the dialysate flow distribution between the
hollow fibers in a conventional dialyzer, one has to develop and
implement additional `static-mixer-like` implants that produce even
and stable dialysate flow. This could potentially enhance the
performance of the dialyzer. Developments in this direction are
already evident in the design of the hollow fiber-type dialyzers
among leading membrane manufacturers. However, MMA and
microlamination technology allow for a much better and easier
realization of an accurately engineered flow on both sides of the
haemodialysis membrane. Moreover, the disclosed embodiments address
major problems (blood cell damage, overall size of the device,
haemotreatment duration, etc.) arising from current practices in
haemodialysis and other haemotreatments.
B. Microscale Dialyzer Embodiment
[0069] One embodiment of a microscale dialyzer 30 is illustrated in
FIG. 3. FIG. 3 illustrates that the disclosed unit has fluid
collection units 32 and 34 and at least one diffusion unit 36. The
entire unit can be made using microlamination techniques. The
diffusion unit 36 of the device can be made as a microchannel
array. A schematic diagram illustrating a microchannel array 40
having a filter membrane integrally associated therewith is
illustrated in FIG. 4. The illustrated embodiment 40 includes an
array of microchannels 42 for blood flow and dialysate flow. These
fluids are separated by a membrane 44, particularly a
semi-permeable membrane, such as the NCC-polymeric composite
membrane described above. A particular embodiment includes a
nanocrystalline-cellulose/polysulfone membrane. The cross section
of the microchannels 42 can be varied, as indicated in FIG. 4 to
provide desired fluid flow characteristics and other beneficial
properties.
[0070] One embodiment of a MECS dialyzer design 50 is illustrated
in FIG. 5. The size of the device is only 2-3 times the size of a
dime (indicated by the coin placed adjacent the device in FIG. 6 of
the priority provisional application incorporated herein be
reference) for size comparison.
[0071] The combination of biocompatibility, stiffness and nanoscale
filler dimensions afforded by cellulose nanocrystal-filled PSf
allow the incorporation of microscale features (1-100 .mu.m) in the
MECS devices.
[0072] FIG. 5 illustrates the use of mixing posts 52 prior to the
microchannels 54. The posts 52 provide a method for dispersing
blood flow evenly throughout available microchannels 54 through
which the blood will flow. These posts 52 can be physical portions
of the device 50. For example, in the illustrated embodiment the
posts 52 are triangularly shaped, and extend upwardly from a
surface to impinge a fluid flowing over and about the posts. These
posts 52 can have any geometric shape in addition to the triangular
posts illustrated in cross section, including without limitation,
cylindrical, rectangular, square, polygonal, and any combination of
such shaped posts. The spacing and number of posts provided is
determined by the desired end result, i.e. distribution of blood
flow substantially equally among the available microchannels.
[0073] Other methods also can be used to disperse blood flow evenly
within the microchannels. For example, the surface in contact with
the fluid flow, such as blood flow, can be modified to have regions
that are compatible with the flowing fluid and regions that are not
compatible with the flowing fluid. Again by way of example, regions
of the dialyzer surface can be made either hydrophobic or
hydrophilic by surface modification. For dialysis, regions of the
surface that are hydrophobic tend to repel the blood flow and
thereby allow blood dispersion into the microchannels, much in the
same manner as the mixing posts illustrated in the embodiment of
FIG. 5.
[0074] The microchannels in the illustrated embodiment have a blood
flow side and a dialysate flow side. FIG. 6 is a plan view of a
microchannel dialyzer 60, the blood flow side, side 62, and the
dialysate flow side, side 64.
[0075] Illustrated embodiments of the present dialyzer unit
typically are fabricated as a multilayered unit. These features are
illustrated schematically in FIG. 7. The embodiment 70 depicted by
FIG. 7 includes a top support plate 72 and a bottom support plate
74. Between the two support plates 72 and 74 are plural
microchannel-defining plates. Three types of microchannel-defining
plates are used to make the layered design illustrated in FIG. 7: a
top, one-sided plate 76; plural middle, two-sided plates 78; and a
bottom, one-sided plate 80. Positioned between the plural plates
76-80 are filter membranes 82, such as the nanocrystalline
cellulose/polysulfone composite filter membrane described
herein.
[0076] Diffusion channels can have a variety of configurations.
Different diffusion units may have different microchannel
configurations. Alternatively, a single diffusion unit of a
disclosed dialyzer embodiment can have plural different
microchannel configurations. Plural different channel
configurations 82, 84 and 86 are schematically illustrated in
device 83 of FIG. 8.
[0077] The dimensions of plural plates used to assemble a dialzyer
unit also can vary to provide different functional results. Typical
dimensions in microns used to make the plates illustrated in FIGS.
7 and 8 are provided by plates 92-100 of FIG. 9. A person of
ordinary skill in the art will appreciate that these dimensions can
be varied and still provide an operating dialzyer unit.
[0078] A schematic diagram illustrating one embodiment 100 of an
overall dialyzer system is provided as FIG. 10. A device 102 for
flowing blood to the microchannel-based dialysis unit, and a device
104 for flowing fluid to the dialysate side, are provided. In the
illustrated embodiment, syringe pumps 102, 104 are fluidly coupled
to the inlet sides 108, 110 of the microchannel-based dialysis unit
106. Optional pressure controllers 112, 114 can be placed in-line
between one or more of the syringe pumps 102, 104 and the
microchannel-based dialysis unit 106. Moreover, where necessary or
desired, fluid flow controllers 116, 118 can be used to control
fluid flow to one or more of the components of the system.
[0079] The microchannel-based dialysis unit 106 receives the
fluids, which are separated into a blood flow side and a dialysate
side. Different degrees of separation can occur in the disclosed
unit. For example, a first separation may involve blood separation,
whereby primarily blood cells are separated from the blood side
leaving a remaining fluid having both biologically necessary
components, such as proteins, as well as waste products, such as
urea. This remaining fluid then can be subjected to additional
dialysis to remove materials, such as urea, that are normally
removed during dialysis. The blood cell stream and the remaining
purified fluid stream then can be recombined for return to the
patient.
[0080] As would be understood by a person of ordinary skill in the
art, additional devices, such as analytical or computational
devices, can be used in combination with the dialysis embodiment
described herein. For example, one or more computers 120 can be
used to acquire data, monitor system operation, fluid composition,
etc. The embodiment 100 illustrated in FIG. 10 also includes an
analytical separation device, such as a high pressure liquid
chromatography device 122.
[0081] A test device 1100 has been assembled to test
microchannel-based fluid filtration. A cross sectional schematic
view of such a test device 1100 is provided as FIG. 11. This test
unit 1100 allows an operator to test different membranes for fluid
separation. The test unit 1100 comprises a blood inlet 1102 and
outlet 1104 and a dialysate inlet 1106 and outlet 1108. Fluid flow
occurs through a quartz window 1110, which allows the operator
and/or a camera 1112 to monitor fluid flow through the device 1100.
Fluid flow is directed adjacent the two major planar surfaces 1116,
1118 of a separation membrane 1114, such as the
nanocrystilline-cellulose/polysulfone composite membrane described
herein.
[0082] A reactor has been developed to demonstrate operation of a
dialyzer as disclosed herein. A schematic exploded view of one
embodiment of a reactor 1200 is provided as FIG. 12. The reactor
1200 comprises a holder for the separation device, which comprises
plural microchannel plates with a semipermeable membrane between
them. The reactor allows interfacing the test separation device to
other system components, such as pumps, tubing, reservoirs, etc.
The illustrated reactor 1200 includes two end plates 1202, 1204.
Gaskets 1206 and 1208 are positioned adjacent end plates 1202, 1204
for fluidly sealing the reactor 1200. Quartz windows 1210, 1212 are
provided through which reactor operation can be monitored. Spacers,
such as Teflon spacers 1214 and 1216, and a flow separator 1218 are
provided to effectively space the reactor components. A photograph
of a disassembled working embodiment of the reactor, adjacent a
coin for size comparison, was provided as FIG. 14 in the priority
provisional application.
[0083] Reactor 1200 is fluidly coupled to two fluid mixtures. These
fluid mixtures are flowed through the reactor 1200 using a pump.
Fluid flowing through the reactor 1200 flowed adjacent a membrane,
thereby establishing that the combination of microfluidic channels
and a membrane function usefully as a fluid separation/purification
device.
III. Making Disclosed MECS Filtration Devices
A. Microlamination Method--General Discussion
[0084] Devices disclosed herein may be produced by a fabrication
approach known as microlamination. Microlamination methods are
described in several patents and pending applications commonly
assigned to Oregon State University, including U.S. Pat. Nos.
6,793,831, 6,672,502, and U.S. patent applications, Nos.
60/514,237, entitled High Volume Microlamination Production Of Mecs
Devices, and 60/554,901, entitled Microchemical Microfactories, all
of which are incorporated herein by reference.
[0085] Microlamination consists of patterning and bonding thin
layers of material, called laminae, to generate a monolithic device
with embedded features. Microlamination involves at least three
levels of production technology: 1) lamina patterning, 2) laminae
registration, and 3) laminae bonding. Thus, the method of the
present invention for making devices comprises providing plural
laminae, registering the laminae, and bonding the laminae. The
method also may include dissociating components (i.e.,
substructures from structures) to make the device. Component
dissociation can be performed prior to, subsequent to, or
simultaneously with bonding the laminae.
[0086] In one aspect of the invention, laminae are formed from a
variety of materials, particularly metals, alloys, including
intermetallic metals and alloys, polymeric materials, including
solely by way of example and without limitation, PDMS,
polysulfones, polyimides, etc., ceramics, and combinations of such
materials. The proper selection of a material for a particular
application will be determined by other factors, such as the
physical properties of the metal or metal alloy and cost. Examples
of metals and alloys particularly useful for metal microlamination
include stainless steel, carbon steel, phosphor bronze, copper,
graphite, and aluminum.
[0087] Laminae useful for the microlamination method of the present
invention can have a variety of sizes. Generally, the laminae have
thicknesses of from about 1 mil to about 32 mils thick, preferably
from about 2 mils to about 10 mils thick, and even more preferably
from about 3 to about 4 mils thick (1 mil is 1 one-thousandth of an
inch). Individual lamina within a stack also can have different
thicknesses.
B. Laminae
1. Lamina Patterns
[0088] Lamina patterning may comprise machining or etching a
pattern in the lamina. The pattern produced depends on the device
being made. Without limitation, techniques for machining or etching
include laser-beam, electron-beam, ion-beam, electrochemical,
electrodischarge, chemical and mechanical material deposition or
removal can be used. The lamina can be patterned by both
lithographic and non-lithographic processes. Lithographic processes
include micromolding and electroplating methods, such as LIGA, and
other net-shape fabrication techniques. Some additional examples of
lithographic techniques include chemical micromachining (i.e., wet
etching), photochemical machining, through-mask electrochemical
micromachining (EMM), plasma etching, as well as deposition
techniques, such as chemical vaporization deposition, sputtering,
evaporation, and electroplating. Non-lithographic techniques
include electrodischarge machining (EDM), mechanical micromachining
and laser micromachining (i.e., laser photoablation). Photochemical
and electrochemical micromachining likely are preferred for
mass-producing devices.
[0089] A currently preferred method for patterning lamina for
prototyping devices is laser micromachining, such as laser
numerically controlled micromachining. Laser micromachining has
been accomplished with pulsed or continuous laser action in working
embodiments. Machining systems based on Nd:YAG and excimer lasers
are typically pulsed, while CO.sub.2 laser systems are continuous.
Nd:YAG systems typically were done with an Electro Scientific
Industries model 4420. This micromachining system used two degrees
of freedom by moving the focused laser flux across a part in a
digitally controlled X-Y motion. The laser was pulsed in the range
of from about 1 kHz to about 3 kHz. This provides a continuous cut
if the writing speed allows pulses to overlap. The cutting action
is either thermally or chemically ablative, depending on the
material being machined and the wavelength used (either the
fundamental at 1064 nm, the second harmonic at 532 nm, the third
harmonic at 355 nm or the fourth harmonic at 266 nm). The drive
mechanism for the Nd:YAG laser was a digitally controlled servo
actuator that provides a resolution of approximately 2 .mu.m. The
width of the through cut, however, depends on the diameter of the
focused beam.
[0090] Laminae also have been machined with CO.sub.2 laser systems.
Most of the commercial CO.sub.2 lasers semi-ablate or liquefy the
material being cut. A high-velocity gas jet often is used to help
remove debris. As with the Nd:YAG systems, the laser (or workpiece)
is translated in the X-Y directions to obtain a desired pattern in
the material.
[0091] An Nd:YAG pulse laser has been used to cut through, for
example, 90-.mu.m-thick steel shims. The line widths for these cuts
were approximately 35 .mu.m wide, although with steel, some
tapering was observed. For the 90-.mu.m-thick sample, three passes
were made using 1 kHz pulse rate, an average laser power of 740 mW,
and a distance between pulses of 2 .mu.m. Also, the cuts were made
at 355 nm. Some debris and ridging was observed along the edge of
the cut on the front side. This material was easily removed from
the surface during lamina preparation, such as by surface
polishing.
[0092] Laminae also have been patterned using a CO.sub.2 laser. For
example, a serpentine flexural spring used in a miniature Stirling
cooler has been prepared using a CO.sub.2 laser. The CO.sub.2
through-cuts were approximately 200 .mu.m wide and also exhibited a
slight taper. The width of the CO.sub.2 laser cut was the minimum
achievable with the system used. The part was cleaned in a lamina
preparation step using surface polishing to remove debris.
[0093] Pulsed Nd:YAG lasers also are capable of micromachining
laminae made from polymeric materials, such as laminae made from
polyimides. Pulsed Nd:YAG lasers are capable of micromachining
these materials with high resolution and no recast debris.
Ultraviolet wavelengths appear best for this type of work where
chemical ablation apparently is the mechanism involved in removing
material. Clean, sharp-edged holes in the 25-50 .mu.m diameter
range have been produced.
2. Lamina Preparation
[0094] In another aspect of the invention, lamina patterning
includes lamina preparation. The laminae can be prepared by a
variety of techniques. For example, surface polishing of a lamina
following pattern formation may be beneficial. Moreover, acid
etching can be used to remove any oxides from a metal or alloy
lamina. In one embodiment of the invention, lamina preparation
includes applying an oxide-free coating to some or all of the
laminae. An example of this would be electroplating gold onto the
lamina to prevent oxidation at ambient conditions.
[0095] In another embodiment of the invention, lamina preparation
includes filling the spaces between the structures and
substructures with a material, referred to herein for convenience
as a fixative, that holds the structure and substructure together
before bonding the laminae and after the fixture bridges are
eliminated. For instance, investment casting wax can be used as the
fixative to hold together the structure and substructure. The
fixture bridges are then eliminated, and the substructure is
maintained in contact with the structure by the fixative. The
fixative is eliminated during or after bonding the laminae
together, thus dissociating the substructure from the
structure.
3. Laminae Registration
[0096] Laminae registration comprises (1) stacking the laminae so
that each of the plural lamina in a stack used to make a device is
in its proper location within the stack, and (2) placing adjacent
laminae with respect to each other so that they are properly
aligned as determined by the design of the device. It should be
recognized that a variety of methods can be used to properly align
laminae, including manually and visually aligning laminae.
[0097] The precision to which laminae can be positioned with
respect to one another may determine whether a final device will
function. The complexity may range from structures such as
microchannel arrays, which are tolerant to a certain degree of
misalignment, to more sophisticated devices requiring highly
precise alignment. For example, a small scale device may need a
rotating sub-component requiring miniature journal bearings axially
positioned to within a few microns of each other. Several alignment
methods can be used to achieve the desired precision. Registration
can be accomplished, for example, using an alignment jig that
accepts the stack of laminae and aligns each using some embedded
feature, e.g., corners and edges, which work best if such features
are common to all laminae. Another approach incorporates alignment
features, such as holes, into each lamina at the same time other
features are being machined. Alignment jigs are then used that
incorporate pins that pass through the alignment holes. The edge
alignment approach can register laminae to within 10 microns,
assuming the laminae edges are accurate to this precision. With
alignment pins and a highly accurate lamina machining technique,
micron-level positioning is feasible.
[0098] Thermally assisted lamina registration also can be used as
desired. Additional detail concerning thermally assisted lamina
registration is provided by copending application No. 60/514,237,
which is incorporated herein by reference.
[0099] Registration of laminae in a working embodiments typically
was accomplished using an alignment jig or by thermal registration.
If an alignment jig is used, it must tolerate the bonding step.
Thus, in typical microlamination setups, the alignment jig
preferably was incorporated into the design of the structure that
compressed the stack for bonding. A person of ordinary skill in the
art also will recognize that the registration process can be
automated.
C. Laminae Bonding
[0100] Laminae bonding comprises bonding the plural laminae one to
another to produce a monolithic device (also referred to as a
laminate). Laminae bonding can be accomplished by a number of
methods including, without limitation, diffusion soldering/bonding,
thermal brazing, adhesive bonding, thermal adhesive bonding,
curative adhesive bonding, electrostatic bonding, resistance
welding, microprojection welding, and combinations thereof.
1. Microprojection welding
[0101] Laminae can be bonded to one another at specific sites on
the laminae by the novel process of microprojection welding.
Microprojection welding comprises patterning lamina having at least
one projection, and more typically plural projections, that extends
from at least one surface, generally a major planar surface, of the
lamina. Selective bonding is accomplished by placing laminae
between electrodes and passing a current through the electrodes.
The laminae are bonded together selectively at the site or sites of
the projection(s). A person of ordinary skill in the art will
recognize that a variety of materials suitable for welding can be
used to produce the projections, including mild steel, carbon
steel, low carbon steel, weldable stainless steel, gold, copper,
and mixtures thereof. The welding material (i.e., projections)
preferably is made of the same material as the laminae being
bonded.
[0102] Microprojections suitable for microprojection welding can be
produced by both additive and subtractive processes. In one
embodiment of the invention, a subtractive process was used to
pattern laminae. The subtractive process comprises etching away
material from a lamina to produce the microprojections. A person of
ordinary skill in the art will recognize that a variety of etching
processes can be used, including photochemical and electrochemical
etching.
[0103] In another embodiment of the invention, microprojections can
be produced on laminae by an additive process. This additive
process comprises building up a lamina to form the microprojections
or building up the projections on a lamina prior to lamina
patterning. One method of patterning the microprojections would
involve either etching or depositing projections through a
lithographic mask prior to lamina production. Lamina patterning
should then be conducted with reference to the placement of these
projections. For example, if the flapper valve pivot is too close
to ring projections, then "flash material" may interfere with the
operation of the flapper valve. "Flash material" is extraneous
projection weld material or material produced by the welding
operation.
[0104] Microprojections can have several geometries. For example,
individual isolated protrusions can be used. Moreover, continuous
lines, rings or any other geometries suitable for the welding
requirements of a particular device, can be used to practice
microprojection welding of laminae.
[0105] In one aspect of the invention, plate electrodes were used
to deliver current sufficient to weld the laminae to one another.
The laminae that are to be welded together are placed between and
in contact with the plate electrodes. Optionally, pressure can be
applied to place the laminae in contact with each other or the
plate electrodes.
[0106] Typical projections of working embodiment had heights of
from about 100 .mu.M to about 200 .mu.m, with diameters of about
125 .mu.m or less. If the projections are shorter than 100 .mu.m,
electrical shorts may result. The weld nuggets produced by the
welding operation had diameters of about 1.5-1.7 mm. It can be
important to orient substructures on individual lamina so that weld
nuggets patterned by the welding process do not overlap, and hence
potentially interfere with the operation of, the substructures.
2. Diffusion Soldering
[0107] Diffusion soldering is a known method for filing joints.
See, for example, D. M. Jacobson and G. Humpston, Diffusion
Soldering, Soldering & Surface Mount Technology, No. 10, pp.
27-32 (1992), which is incorporated herein by reference. However,
diffusion soldering has not been adapted for use in microlamination
processes for bonding laminae one to another for MECS devices.
[0108] Diffusion soldering of laminae can be practiced using a
number of material combinations, including both base metals and
alloys and on surfaces that have been metalized. Two of the more
versatile combinations are tin-silver and tin-indium. These two
diffusion-soldering systems provide a low-temperature bonding
process that results in intermetallic strong joints at the material
interface.
[0109] Another attractive feature is that the bond produced by
diffusion soldering can take considerably higher reheat
temperatures than most conventional bonding methods. Because of
these characteristics, diffusion soldering is well suited for
producing microlaminated devices that must operate at moderate
temperatures (i.e., up to approximately 500.degree. C.).
[0110] The tin-silver system can work on any surface able to
withstand moderate temperatures and capable of receiving a plating
layer of the requisite metal. For many devices, steel and stainless
steel offer a number of attractive characteristics for fatigue
strength, magnetic properties, relatively low thermal conductivity
(for stainless steel), and corrosion resistance.
[0111] The diffusion soldering method first comprises preparing and
plating the surface of each lamina. A typical plating process
comprises plating with a low temperature material and a high
temperature material. These two materials typically form an
intermetallic material by diffusion soldering.
[0112] More specifically, diffusion soldering may involve placing a
first strike layer, such as a thin strike layer of nickel
(approximately 0.5 .mu.m) on a bare surface that will receive the
nickel, such as a metal or alloy surface. This layer promotes
adhesion of the other platable metals. Strike layers may not be
necessary. Then, a second, generally thicker layer, such as a
silver layer 1 .mu.m-10 .mu.m, more typically 2-5 .mu.m thick, is
plated over the first layer. Copper may be preferred as a bonding
agent between the strike layer or the lamina and the high
temperature soldering material because of its ability to readily
bond to both nickel and silver. Copper can create a copper-silver
intermetallic that is weaker than the surrounding material, and
hence be the site of material failure in the device. Finally, a
third low-temperature material layer, typically tin, is plated 1
.mu.m-10 .mu.m, preferably 2-5 .mu.m thick over the second
layer.
[0113] Working embodiments used a stack having alternating surfaces
plated with either high-temperature or high-temperature and
low-temperature material, such as silver or silver and tin. The two
outside laminae typically have high-temperature material, such as
silver, so that the final, bonded stack did not adhere to the
alignment jig. If possible, non-bonded internal structures and
cavities preferably have the silver layer on their surface. This is
to prevent low-temperature material from flowing into features.
[0114] The bonding takes place by momentarily raising the stack
temperature above the melting point of the low-temperature material
(e.g., tin @ 232.degree. C.) under a compression pressure
sufficient to achieve the bond. At higher pressures, lower
temperatures likely will be required to achieve adequate bonding.
Working embodiments have used compression pressures of
approximately 2 MPa to about 5 MPa. A compression pressure below
about 2 MPa may not provide sufficient pressure to achieve adequate
bonding. Air and other oxidizing atmospheres preferably are
excluded at this point to avoid the creation of tin oxides and
voids. However, with the surface properly prepared, the bonding
process is rapid and complete. One important aspect is to maintain
sufficiently low temperatures and pressures so that the lower
temperature material does not flow into the features, causing
restriction of flow therethrough or therein.
[0115] Bond strength and re-heat temperatures can benefit by
heating the stack for a longer period of time at the bonding
temperature, such as at least up to one hour. This allows tin to
further diffuse into the silver and form stronger intermetallic
compounds within the joint itself. Some evidence exists for
ultimately forming a silver bond interspersed with intermetallic
tin/silver particles yielding a high strength, moderate temperature
joint. Indium can be used in place of tin to yield an even lower
temperature (melting point of indium is 157.degree. C.) bonding
process.
3. Miscellaneous Bonding Methods
[0116] Polyimide sheet adhesives can be used to bond laminae
together. Polyimide is a commercially available, high-strength,
high-temperature polymer. For example, Dupont manufactures a
polyimide sheet adhesive, Kapton KJ. Kapton KJ retains adhesive
properties and can bond surfaces together when heated and
compressed. Polyimide sheets form moderate strength bonds that also
provide good sealing capability.
D. Component Dissociation by Eliminating Fixture Bridges
[0117] Component dissociation is accomplished by eliminating
fixture bridges. It will be recognized that there are a variety of
ways to eliminate fixture bridges, including vaporizing the fixture
bridge by heating it to a sufficient temperature, chemically
eliminating, such as by dissolving, the fixture bridge, and laser
ablation of the fixture bridge. Combinations of these methods also
can be used.
[0118] One method for vaporizing the fixture bridges comprises
capacitive discharge dissociation. Capacitive discharge
dissociation comprises applying a current through the fixture
bridge sufficient to vaporize the fixture bridge. There are a
variety of ways to apply current through a fixture bridge. Working
embodiments of the method have placed a first electrode in contact
with the structure and a second electrode in contact with the
substructure to be dissociated. Current is passed between the
electrodes.
[0119] In one embodiment of the invention, a DC power source was
used to charge a capacitor. The capacitor was discharged to pass
current through the electrodes. The temperature, the amount of
current, and the power necessary to eliminate the fixture bridge
often varies with the particular properties of the fixture bridge,
including the material the fixture bridge is made of, its
cross-sectional area, and its length.
[0120] In another embodiment of the invention, fixture bridges are
eliminated by thermochemical dissociation. Thermochemical
dissociation has the potential advantage of reducing debris that
may form during fixture bridge elimination. Thermochemical
dissociation comprises selectively heating the fixture bridges, in
combination with chemical elimination. Selective heating of the
bridge can be accomplished by applying current to the fixture
bridge, heating with a laser and/or focusing a laser on the bridge.
One way to apply current through the fixture bridge comprises
placing electrodes at or near the ends of the fixture bridge and
passing a current between the electrodes. In another embodiment of
the invention, heating elements, or some other method for
delivering thermal energy, can be used to selectively heat the
fixture bridges.
[0121] Chemical elimination also comprises applying a sufficient
amount of a chemical to eliminate the fixture bridges. The fixture
bridges also optionally can be selectively heated to a temperature
sufficient to help chemically eliminate them either prior to,
subsequent to, or simultaneously with application of the chemical.
There are a variety of chemicals that can be used to eliminate the
fixture bridges, such as acids, particularly mineral acids, bases,
oxidizing agents, and mixtures thereof. The concentration, pH, and
temperature sufficient to selectively chemically eliminate the
fixture bridges varies with the particular properties of the
fixture bridge, including the material the fixture bridge is made
of, the cross-sectional area, and the length. Preferably, an acid
having a pH of less than about 3 and at a temperature above
freezing temperature is applied to the lamina. Preferably, the
fixture bridges are heated to temperatures from about 200.degree.
C. to about 300.degree. C. If the laminae are made of a copper
alloy, cupric chloride or ferric chloride can be used to chemically
eliminate the bridge. If the laminae are made of steel, a mixture,
such as a 1:1 volume mixture of HCl:HNO.sub.3, can be used to
eliminate the fixture bridge.
[0122] In another embodiment of the invention, fixture bridges are
eliminated by laser ablation. In this embodiment, line-of-sight
access to the fixture bridges from the exterior of the device is
desired. The laser beam should be able to be focused onto the
fixture bridge, which may require line-of sight access. UV lasers
are particularly useful as they ablate metals as well as polymers
and ceramics with little heat affect and very sharply distinguished
features. Laser ablation allows the fabrication of preassembled
features in materials other than metals, such as polymer and
ceramics. An Nd:YAG laser operating in the fourth harmonic (266 nm
wavelength) would be an example of a UV laser with sufficient power
to perform this operation.
[0123] Fixture bridges can be eliminated either prior to,
subsequent to, or simultaneously with bonding of the plural
laminae. In one embodiment of the invention, the fixture bridges
are eliminated prior to the bonding of the plural laminae one to
another.
[0124] The method of this invention can be used to fabricate
freeform geometries and microfeatures within a device.
Microfeatures are of the size of from about 1 .mu.m to about 100
.mu.m. The methods of the invention can be used to produce
micro-scale and meso-scale devices. Micro-scale devices are of the
size of from about 1 .mu.m to about 1 mm, preferably from about 1
.mu.m to about 500 .mu.m, and even more preferably from about 1
.mu.m to about 100 .mu.m. Meso-scale devices are of the size of
from about 1 mm to about 10 cm, preferably from about 1 mm to about
5 cm, and even more preferably from about 1 mm to about 1 cm.
Arrays of preassembled, meso-scale devices can be fabricated with
overall sizes of up to about 12.5 centimeters by about 12.5
centimeters.
IV. Bonding Heterogeneous Stacks of Polymers
A. Novel methods for bonding heterogeneous stacks of polymers
[0125] Filtration units, such as a portable kidney dialysis unit,
are bulk microfluidic devices because of the relatively larger
volumes of fluid that are processed in microchannels over
traditional "lab-on-a-chip" technology. Microchannel cross-sections
can be produced to handle these fluid flows using highly-parallel
arrays of microchannels. FIG. 13 provides an indication of the
different uses for MECS and micrototal analysis systems
(.mu.TAS).
B. Requirements for membrane integration
[0126] MECS devices may integrate various types of membranes within
a microlaminated stack. Examples include, without limitation:
integrating Pd membranes for hydrogen separation within
microchannel fuel processing systems; integrating contactor
membranes in microchannel absorbers for use in heat pumps;
integrating separation membranes into microchannel dialyzers for
portable kidney dialysis; integrating elastomeric membranes into
highly-branched networks of microreactors for molecular
manufacturing (e.g. dendrimer synthesis); liquid-gas contactor
useful for absorption of a gas, such as oxygen into a liquid, such
as blood; separating CO.sub.2 and/or H.sub.2S from natural gas;
water purification such as by separating organic materials, such as
organic acids from water. In each of these examples, heterogeneous
materials must be integrated into a laminated stack.
[0127] A number of factors typically are considered to integrate
membranes within embedded microchannel systems. For example,
membrane materials generally are quite expensive, and therefore it
is desirable to minimize the amount of membrane material used. This
can be accomplished using a second, less expensive packaging
material that needs to be integrated with the membrane
material.
[0128] Also, membrane materials may have specific nano- or
micro-morphologies which dictate the mass transfer of the membrane.
These morphologies often are sensitive to heat, pressure and other
processing conditions. Therefore, these materials cannot be
conveniently patterned into geometries compatible with microchannel
designs. A mechanism therefore is needed to incorporate the raw
material form within the microlaminated stack.
[0129] Many techniques used to bond together elements made from a
single material are less suitable for bonding together elements
made from different materials. An example might be ultrasonic
welding or thermal bonding of two polymers with significantly
different glass transition temperatures where the structural form
of one is compromised at a temperature lower than would be used for
welding the second polymer. Also, solvent welding is complicated
because different solvents are needed for different materials.
Finally, plasma oxidation produces excellent welds between
polydimethylsiloxane, polyethylene or polystyrene, but cannot be
used effectively for other combinations of materials.
[0130] Membranes often have a thickness, or are made out of a
material, that results in poor stiffness. Consequently, one
non-trivial factor is producing a microchannel array with
interspersing membranes that do not result in significant fin
warpage and channel non-uniformities. Channel non-uniformities can
lead to flow maldistribution, which negatively impacts the
effectiveness of heat exchangers and microreactors.
[0131] The low modulus of some membranes requires that the layers
be thick (on the order of one mm) in order to maintain dimensions.
Therefore, in order to reduce the fluid volume of the MECS device
being developed while meeting its processing and operating
requirements, it is desirable to integrate the elastomeric
capabilities of certain materials, such as PDMS, with a stiff
material.
[0132] While some membranes are excellent candidates as valve
membranes or other purposes, they are not good for packaging. One
issue with separation membranes is that they are highly gas
permeable, which can cause evaporation in microchannels leading to
vapor-lock.
[0133] Another issue is that most membranes are not suitable as
substrates for thin film deposition of heaters and thermocouples.
Therefore, where such devices are required, new methods must be
developed for their incorporation into working devices.
C. Membrane Integration Techniques
PDMS Integration
[0134] One method for bonding PDMS to another surface involves
plasma oxidation of the PDMS surface, followed by conformality to
the faying surface. Plasma oxidation introduces silanol (Si--OH)
groups on the surface of PDMS. The condensation reaction of these
groups with other appropriate functional groups [such as --OH,
--COOH, carbonyls (--C=0), etc.] on the surface of another material
or PDMS forms a strong bond between the two surfaces and
immobilizes the grafted layer. This approach has several problems.
First, the oxidized PDMS surface becomes inactive if not stabilized
in aqueous solution within minutes after plasma oxidation. Second,
it is compatible with only a handful of materials including glass,
silicon, silicon oxide, silicon nitride, polyethylene and
polystyrene. Silicon and glass surfaces are expensive relative to
polymeric surfaces for long-term development. The only two
polymers, polystyrene and polyethylene, which can be grafted to
PDMS are not suitable for thin film deposition. Ticona Topas (COC),
Zeonor 1600 and GE HPS1/HPS2 are examples of structural polymers
having excellent optical clarity, high modulus, high glass
transition temperature (>150.degree. C.) and low gas
permeability suitable for thin film deposition. Therefore,
integration of PDMS with cheap, structural polymers would be highly
desirable.
[0135] One specific approach for integrated PDMS membranes is to
formulate copolymers with protected functionality under atmospheric
conditions, which will polymerize under selective exposure to UV
light. A first procedure concerns hydride functional (Si--H)
siloxanes that have been incorporated into silanol elastomer
formulations to produce foamed structures. Based on this, a novel
and plausible approach to impart bonding character on PDMS, without
plasma oxidation, is to incorporate a small amount (less than 1%)
of silanol functional siloxane (or polysilsesquioxane) into the
vinyl-addition siloxane formulation and selectively cure the blend.
Also, a methacrylate or acrylate functional siloxane copolymer
(which cures on exposure to UV) can be incorporated into the
vinyl-addition siloxane such that selective curing of the blend can
be used to bond surfaces. Oxygen inhibits the polymerization of
methacrylate, but the methacrylate functionality can be protected
in the presence of oxygen and unprotected to obtain a reasonable
cure when blanketed with nitrogen or argon during UV exposure.
D. Physical Constraint
[0136] Another approach to membrane integration is to physically
constrain membrane layers between stiff layers of molded polymers
(e.g. Ticona Topas COC, Zeonor 1600 and GE HPS1/HPS2). Because of
the stiffness of these materials, each makes an excellent candidate
for ultrasonic welding. In addition, as thermoplastics, each has
the ability to be thermally bonded (PDMS has a degradation
temperature well above the Tg of these materials) and solvent
welded.
[0137] Ultrasonic welding has enabled integration of the
microinjection, microreaction, microseparation, detection and
microextraction subsystems within a microreactor design for
synthesizing dendrimer molecules. One goal of this architecture has
been to minimize dead space within the microsystem by using stiff
polymer films in place of thick PDMS substrates used in previous
work for homogeneous PDMS microsystem integration. However, these
same concepts of physical constraint can be extended to many
different heterogenous microlaminated platforms.
E. Ultrasonic Welding
[0138] A current method involves sandwiching a PDMS valve membrane
between two polycarbonate layers using ultrasonic welding. In order
to accomplish this, angled channels are machined into a stainless
steel substrate after Ni electroforming and resist stripping. These
produce raised ridges during embossing that act as energy directors
for ultrasonic welding.
[0139] The elastomer valve membrane layer can be produced by spin
casting a suitable polymeric material or polymeric precursor, such
as a PDMS monomer, onto a wafer with raised photoresist features
that produce the valve chambers. The polymer is then cured.
Openings for protrusion of the ultrasonic energy directors are then
laser machined. It will be understood that this PDMS membrane layer
could be replaced by any off-the-shelf membrane. FIG. 14A is a
schematic, cross-sectional diagram of a microchannel array 1400
having a polycarbonate top plate 1402, and a polycarbonate bottom
plate 1404 with enclosed microchannels 1406. Energy directors 1408
are provided either as separate units, or as defined by plate 1404.
Array 1400 also includes a valve layer, such as a
polydimethylsiloxane layer 1410.
[0140] FIG. 14A illustrates the array 1400 prior to ultrasonically
welding with the energy directors 1408 protruding above the PDMS
layer 1410. FIG. 14B diagrams the result of ultrasonic welding the
array 1400 with the energy directors 1408 melted down, bonding the
top and bottom PC films 1402 and 1404, compressing the PDMS layer
1410 and sealing the microchannels 1406. With appropriate welding
time and pressure the energy directors form strong bonds and the
PDMS compresses to create a conformal seal against the
polycarbonate top and bottom as shown by FIG. 15.
F. Packaging Heterogeneous Stack of Polymeric Materials
[0141] Methods are needed to encapsulate a heterogeneous stack of
materials, such as heterogeneous stacks of lamina made from various
polymeric materials. Two alternative embodiments are disclosed for
enclosing the heterogeneous stack of laminae. First, with the use
of ultrasonic welding, thermal bonding and solvent welding to
physically constrain the membrane across the membrane, the bonding
technique can completely encapsulate the membrane after bonding
with the packaging material. Second, if the bonding process is
unable to fully encapsulate the membrane materials, a dip, spray,
injection, cast or other application of a packaging material can be
used to ultimately encapsulate the device. Care is taken with
regard to fluidic, electrical or other types of interconnect.
G. Membrane Tension
[0142] Flow maldistribution in microchannels can be a significant
problem associated with microfluidic devices. Certain embodiments
of the present invention include a membrane between two adjacent
laminae. The membrane preferably does not deflect substantially
into the microchannel and hence create either channel blockage or
flow maldistributions within the channel. Thus, processes have been
devised to maintain the membrane slightly under tension, such as by
stretching it, and thereafter affixing it in place relative to
adjacent laminae.
[0143] A first method for maintaining a membrane under slight
tension during processing is to mechanically constrain the membrane
under tension. For example, a membrane may be patterned to include
throughcuts for receiving protrusions on a first lamina. The
distance between the two protrusions is slightly greater than the
distance between throughcuts in the membrane. Registering the
membrane with the adjacent lamina(e) so that the protrusions are
inserted into the membrane throughcuts places the membrane in
tension prior to or simultaneously with fixing in place the laminae
and membrane, such as by welding the architecture, to form the
final device.
[0144] There are alternative methods for maintaining the membrane
in tension. For example, a first positive feature might be
patterned into a first lamina to be positioned adjacent the
membrane. The positive feature is sized and shaped to be received
in a receiving slot, i.e., a negative feature, in a second lamina
positioned adjacent the membrane. The positive and negative
features on the adjacent non-membrane laminae preferably provide
substantially equal force to the membrane as they mate. This can be
achieved, for example, by using an O-ring or parallel-line type
configuration. A positive circular or line feature is patterned in
a first lamina and a negative, mating circular pattern or channel
is machined in a second lamina. By coupling together the first
lamina and second lamina so that the positive and negative features
mate, the membrane is both (1) placed under sufficient tension to
minimize or substantially eliminate membrane deflections into the
microchannel, and (2) fixed in position relative to the adjacent
laminae. The tension applied is just that amount of tension that
facilitates minimizing or preventing membrane deflection into
adjacent microchannel. This tension may vary, but likely ranges
from a minimum tension force that is just greater than the material
tension in a layer without application of a tension force to a
maximum force that is below that which would result in material
failure.
[0145] In a commercial production process, the membrane may be
provided reel-to-reel, and hence the membrane material likely is in
limited tension. Thereafter the membrane is positioned relative to
adjacent laminae in a continuous or semi-continuous process.
Alternatively, the membrane may be provided as a sheet. Whatever
the method of deploying the membrane, it is likely that plural
membranes for plural devices will be defined by a single sheet of
polymer. Adjacently positioned packaging laminae also likely will
define plural different components. The stacks may be de-paneled,
whereby excess material in a membrane layer or packaging laminae is
removed, and/or an original number of individual parts as defined
by a single sheet, portion of a sheet and/or laminae, is reduced to
a smaller number by cutting. Eventually, the device must be
singulated from the remaining parts, which also can be done by
laser cutting.
[0146] A second method for maintaining a membrane under tension
comprises placing the membrane in a frame designed to place the
membrane under tension. The frame construction can be patterned
after the O-ring or parallel line type constructions exemplified
above with respect to adjacent laminae. By mating the first and
second frame parts, the membrane material placed between them is
placed under tension. The stretched membrane is then positioned
relative to other laminae to define the final architecture of the
desired device. The membrane material then may be fixed in placed
prior to joining laminae, such as by laser spot welding or solvent
spot welding, followed by joining laminae together, such as by
welding, to form the final device. It also may be possible to weld
the entire device, such as by microwave welding, so that all
laminae are fixed in their positions simultaneously. Microwave
welding is described in copending provisional application No.
60/715,466, which is incorporated herein by reference.
V. Incorporating Other Devices into an Operational System
[0147] Embodiments of the present invention have been disclosed
with reference to filtration and purification methods, and devices
therefore, with one particular embodiment comprising a dialysis
unit. This unit can be coupled with other operating devices to
provide a system useful for a variety of applications. For example,
the system can include a microchemical microfactory for
manufacturing useful biological molecules. The system also can
include, again solely by way of example, micromixers for mixing
fluids that need to be combined, or recombined, such as with the
blood cell and ultrafiltered fluid streams that result from using
the dialysis unit embodiments disclosed herein.
A. Material Synthesis
[0148] Microreactor-based dendrimer production within fractal
nanofactories (or "nanofractories") is disclosed herein, which
allows the ability to control hundreds of parallel reactions
necessary to economically produce dendrimers for societal impact.
Dendrimers are highly-branched, nanometer-sized molecules with
fascinatingly symmetrical fractal morphologies. See FIG. 16. The
word dendrimer (coined by Tomalia et al.) is derived from the Greek
words dendri (branch, tree-like) and meros (part of). Dendrimers
consist of a core-unit, branching units, and end groups located on
their peripheries. Their dendritic architecture presents great
potential for a wide variety of applications. Dendrimers hold great
promise as building blocks for complex supramolecular structures
and as nanoscale carrier molecules in drug delivery, where
nanoparticles and nanocapsules are gaining popularity. The
molecules can be assembled with startling precision, a necessity
when the goal is construction of nanoscale structures or devices
with sophisticated and complex functionality. Along with targeting
tumor cells and drug delivery systems, dendrimers have shown
promising results as tools for MRI imaging and gene transfer
techniques. Also, dendrimer-based nanocomposites are being studied
as possible antimicrobial agents to fight Staphylococcus aureus,
Pseudomonas aeruginosa, and Escherichia coli. The structural
variety of dendrimers, yielding molecules having differing optical,
electrical, and chemical properties, makes them potentially even
more attractive in these applications.
[0149] Dendrimers have been shown to act as scavengers of metal
ions, offering the potential for use in fluid purification, such as
water purification, and environmental clean-up applications. Their
size allows them to be filtered out post-extraction using common
ultrafiltration techniques.
[0150] A critical barrier to the routine use of dendrimers is the
tedious, expensive means of their synthesis. This synthesis
consists of two constantly repeating reaction steps involving: 1)
coupling a central unit to two branching units; and 2) activating
the branches so they can react further. Two general approaches
(divergent and convergent) to dendrimer synthesis exist. Divergent
synthesis starts from a seed and progresses towards the periphery
of the dendrimer, while convergent synthesis proceeds from the
periphery to a core.
B. Divergent Synthesis
[0151] The divergent approach, arising from the seminal work of
Tomalia and Newkome, initiates growth at the core of the dendrimer
and continues outward by the repetition of coupling and activation
steps. In divergent synthesis, several hundred steps may be
required to obtain five or six dendrimer generations (sizes of
interest). In this case the yield for each step multiplies through
to determine the total yield. For example, in the synthesis of a
fifth generation poly (propylene imine) dendrimer (64 imine groups;
248 reactions), a yield of 99% per reaction will result in only
0.99.sup.248=8.27% of defect-free dendrimer. The similar sizes of
defective and defect-free dendrimers then make separation difficult
further complicating matters. Exponential growth in the number of
reactions to be performed to produce higher generations makes
divergent synthesis an unlikely method for the production of
uniform dendrimers beyond generation five or six unless the yield
at each step exceeds 99.8%. In addition, extremely excessive
amounts of reagents are required in latter stages of growth to
reduce side reactions and force reactions to completion. This not
only increases the cost but also causes difficulties in
purification.
C. Convergent Synthesis
[0152] Convergent synthesis, first reported by Hawker and Frechet
in 1989, initiates growth from the exterior of the molecule, and
progresses inward by coupling end groups to each branch of the
monomer. The single functional group at the focal point of the
wedge-shaped dendritic fragment can be activated after the coupling
step. Coupling the activated dendrons to a monomer creates a higher
generation dendron. Finally, the globular multi-dendron dendrimer
is generated by attaching the dendrons to a polyfunctional core.
Here, a small and constant number of reaction sites are maintained
in each reaction step. Consequently, only a small number of side
products are possible in each step. As a result, the reactions can
be driven to completion with only a slight excess of reagent and
defective product can be eliminated prior to subsequent reaction.
Thus, convergent synthesis has the potential to produce purer
dendrons and dendrimers than divergent synthesis. Furthermore, the
ability to precisely place functional groups throughout the
structure, to selectively modify the focal point, and to prepare
well-defined asymmetric dendrimers make the convergent approach
attractive. However, since the coupling reaction occurs only at the
single focal point of the growing dendron, the preparation of
higher generation dendrons and dendrimers (typically above the
sixth generation) is sterically hindered, resulting in decreased
yields. This is especially evident in the reaction between high
generation dendrons and the core. This drawback has limited the
commercialization of dendrimers produced by convergent synthesis.
Our nanofractory approach to convergent synthesis will address this
drawback.
D. Synthesis Using Microsystems
[0153] Chemical synthesis, such as dendrimer synthesis (and
nanoproduction in general), can be facilitated through the improved
process control made available by highly-paralleled,
process-intensified microsystems. Microreaction technology
transforms current batch nanoproduction practices into a continuous
process with rapid, uniform mixing and precise temperature control.
Dendritic macromolecules can be manipulated using micro- and
nanofluidic mixers. Microseparations and microextraction technology
minimize reagent requirements and defective product to further
improve yields in downstream reactions. In addition, microsystems
provide the advantage of eliminating air contact, thereby
minimizing contamination and improving yield. Furthermore,
microsystems technology minimize environmental impact of
nanoproduction using solvent free mixing, integrated separation
techniques and reagent recycling. Finally, the possibility of
synthesizing nanomaterials in the required volumes at the point of
use, eliminates the need to store and transport potentially
hazardous materials.
[0154] Dendrimer production can be implemented within a fractal
nanofactory, or "nanofractory". The nanofractory spatially
intensifies and automates dendrimer production providing strict
control over dendrimer synthesis. This process control enables the
production of higher generation dendrimers to produce novel
materials at higher yields and lower costs. Specific unit
operations are integrated into the fractories including by way of
example and without limitation, micro-scale mixers, separators,
heaters and valves. Implementation of a nanofractory within a
polymer sheet architecture provides the added advantages of an
economical pathway to "numbering up" through microlamination.
E. Micromixer
[0155] In spite of the low purity achievable via divergent
synthesis of higher generation dendrimers, this approach is more
amenable to scale-up than the convergent approach. Polyamidoamine
(PAMAM) is probably the most studied dendrimer today. In 1985 and
1986, Tomalia et al. described the preparation of PAMAMs by the
divergent approach. The synthesis involves in situ branch cell
construction in step-wise, iterative stages around a desired core
(e.g. ammonia or ethylenediamine) to produce defined core-shell
structures. Each generation was synthesized through a reiterative
two-step reaction sequences involving (1) exhaustive alkylation of
primary amines (Michael-type addition) with methyl acrylate and (2)
amidation of amplified ester groups with a large excess of
ethylenediamine to produce primary amine terminal groups. The first
reaction sequence on the exposed dendron creates G=0. Iteration of
the alkylation/amidation sequence produces an amplification of
terminal groups from 1 to 2 with in situ creation of a branch cell
at the anchoring site of the dendron that constitutes G=1.
Conventionally, in order to achieve a high degree of product
purity, the potential synthetic problems associated with amine
additions to esters, including lactam formation, retro-Michael
reactions, incomplete addition, and intermolecular coupling, were
minimized using excess diamine, maintaining moderate reaction
temperatures, and avoiding aqueous solvents. A recent ESI-MS
(Electrospray Ionization Mass Spectrometry) study on PAMAM at the
4.sup.th generation indicated that the sample under analysis
possessed purity no more than 8%.
[0156] Microreaction technology offers several new opportunities to
suppress competing side reactions and maximize product purity.
These include uniform and precise temperature control and low
moisture permeability to avoid water content. Most importantly, the
key is to increase the conversion rate of the alkylation/amidation
reaction sequence through enhancement of effective collision
between reactants. Thus, it is beneficial to create a microfluid
(mixing of reactants at the molecular level) rather than a
macrofluid (aggregates of separate reactants).
[0157] Mixing typically involves integration of one or more fluids
into one phase and molecular diffusion is usually the final step in
all mixing processes. A simple estimation shows that it will take
five seconds to mix two contacting 100 .mu.m thick aqueous laminar
layers containing small molecules and would only take 50
milliseconds if the layers were 10 .mu.m. The essence of mixing
thus relies on the concept of volume division. One common approach
to achieve volume division is creating a turbulent flow. It is
difficult to achieve uniform mixing at the micrometer scale in a
short time by traditional mixing apparatus, such as paddles or
propellers in a reaction tank. Micromixers offer features which
cannot be easily achieved by macroscopic devices, such as ultrafast
mixing on microscale. For example, Bokenkamp et al. fabricated a
micromixer as a quench-flow reactor to study fast reactions
(millisecond time resolution).
[0158] Alkylation and amidation reactions for dendrimer synthesis
will be performed using different micromixers, such as an
interdigital micromixer. A schematic perspective diagram of one
embodiment of an interdigital micromixer 1700 is shown in FIG. 17.
Fluids A and B to be mixed are introduced into the mixing element
1702 as two counter-flows 1704, 1706. Flows 1704 and 1706 enter
interdigital channels (.about.20 to 50 .mu.m) 1708, and split into
many interpenetrated substreams 1710. The substreams 1710 leave the
interdigital channels 1708 perpendicular to the direction of the
feed flows, initially with a multilayered structure. Fast mixing
through diffusion soon follows due to the small thickness of the
individual layer. Silicon-based interdigital type mixers described
in the technical literature can be made using a polymeric
microlamination architecture using replica molding/polymer
embossing and various bonding strategies. Spacing between digits on
the order of 20 .mu.m can be achieved, which provides mixing times
on the order of a few hundred milliseconds depending upon flow
rates. This has been tested by generating cadmium sulfide (CdS)
nanoparticle solution using a PDMS interdigital micromixer. Stable
monodispersed CdS nanoparticle suspensions were produced even
without adding stabilizers.
[0159] Micromixers can be engineered to control the orientation of
higher generation dendrons upon mixing. Two types of micromixers
are particularly promising. One is based on the collision of two
high-energy substreams and the other is based on the injection of
multiple microjets (or nanojets) into a mixing chamber. Membranes
with straight-through pores down to 5 .mu.m have been laser
micromachined in 75 .mu.m thick Kapton KJ and micromolded in 40
.mu.m thick PDMS. Even at 100 .mu.m spacing between pores at a mass
flux of 0.5 g/min/cm.sup.2, pressure drop across the membrane has
been measured to be only a few torr.
[0160] FIG. 19 shows a schematic diagram of an exemplary analytical
micromixer 1900 with a NSOM (Near-field optical microscopy) ear
optical fiber probe 1902. Micromixer 1900 provides for flow 1904
and 1906 to plural microjets 1908. A resulting mixture stream 1910
flows from the microjets 1908. Other analytical micromixers based
on different mixing principles will also be built and studied.
[0161] Location-specific production and immobilization of
dendrimer-templated sorbents in-situ will be used in microfluidic
devices for separations. This same method can be used to build
nanopreparative separators in specific locations in the
nanofractory. This recursive design will employ the dendrimer as a
template in porous polymer sorbent synthesis. This new technology
for the preparation of porous monolithic sorbents will provide
enhanced control over surface chemistry and porosity, and enhance
separations.
[0162] PDMS microchips provide useful surface chemistry for ligand
attachment if first exposed to an oxygen plasma. Such exposure
introduces silanol groups that are useful to bond adjacent device
components and to attach polymers and other ligands to the surface
in the flow conduit. In the former role the silanols condense with
complementary functional groups on other surfaces (such as quartz,
glass, other PDMS components, etc.) to yield a stable, leak-free
seal. In the latter role the activation chemistries described above
are available for use in coupling primary-amine-containing ligands.
In the event that an insufficient surface coverage of silanols
exist for effective immobilization of sorbents, SiO.sub.2 doped
PDMS matrices and matrices incorporating both PDMS and --NH.sub.2
or --OH terminated PDMS may be employed. Several other reasonable
approaches to surface activation and ligand immobilization
exist.
F. Integrating Microscale Separations Devices into the
Nanofractory
[0163] Although others have demonstrated integrated systems for
analysis--systems incorporating multiple mixing, separations,
injection, and detection steps--no example apparently is yet known
in the literature for a highly integrated manufacturing
microdevice. Such a device likely would include reagent delivery,
mixing, heating, reaction, purification, isolation, and transport
elements into a single device. Further, these operations may need
to be iterated multiple times to yield a complex product. The
separative components described herein, capable of extractions and
chromatography, shall be integrated into the nanofractory
architecture.
[0164] Prior efforts have shown the ability to integrate injection
systems with multiple separators, mixers and separators or reactors
and separators on a single chip. Also, efforts have been made to
integrate cell lysis, PCR amplification, separation and detection
on one chip for DNA analysis. These integrations were all performed
on a single glass chip using a cruciform channel design. Surface
area to volume (SAV) ratios for these designs were on the order of
0.005 mm.sup.2/mm.sup.3.
VI. Fractal Microchannels
[0165] The large, fractal sequence of reactions necessary for
convergent dendrimer production lends itself to the implementation
of a fractal nanofactory, or "nanofractory" illustrated by FIGS. 20
and 21.
[0166] The nanofractory actually mimics the geometry of the
dendritic molecule it produces. Fractal microchannels have been
proposed in heat transfer applications to lower pumping powers and
improve thermal distribution on heat transfer surfaces. These
benefits derive mainly from the minimization of microchannel flow
path lengths and the continual disruption of hydrodynamic and
thermal boundary layers caused by the regular bifurcation of the
flow. The space efficiency of fractal networks is used to improve
the channel and unit operation packing density, thereby making the
nanofractory compact. Chamber dimensions for the disclosed
embodiment will be on the order of 50 to 100 .mu.m dictated largely
by mixing times, flow rates, residence times, etc.
[0167] An alternate approach to nanofractory development is shown
in FIG. 21. This modular approach could be used for both divergent
and convergent synthesis. Microarrays 2100 may include plural
layers 2102. The array 2100 of FIG. 21B includes thin film heaters
2104 adjacent a microchannel and a mixing array 2106 to support
material synthesis. Thin films 2104 are evaporated onto substrates
and integrated into microchannels using various bonding
methods.
[0168] Modular microchannel packages will be developed using a Si
bulk micromachining/anodic bonding architecture or soft lithography
techniques. FIG. 27 of the priority provisional application
illustrates a single cruciform set of channels made by soft
lithography with a cross-section nominally 40 .mu.m square that was
used for dendrimer templating of a chromatographic channel.
Further, PDMS substrates may be used as mandrels for replica
molding polyurethane (cross-linked) or vacuum casting polyethylene
(thermoplastic) devices in modest volumes. A replicated substrate
with nominally 100 .mu.m bifurcated flow paths from a
chemically-etched 304 stainless steel substrate also has been made.
The replica is low-density polyethylene (LDPE) and was reproduced
to a dimensional accuracy of 5%.
[0169] Strategies for reagent injection and extraction will be
based on mechanical valves developed by Thorsen, et al., which have
been implemented in high densities (i.e. more than 3500 valves in
625 mm.sup.2) in PDMS architectures. Based on this, it is expected
that mechanical injection and extraction will be more space
efficient than other chemical means of injection (via
electrokinetic pumping) or extraction (via liquid-liquid
extraction), which may require channel lengths on the order of tens
of mm. Second, while the level of valve integration reported in the
literature is currently impressive, the surface-area-to-volume
(SAV) ratio for these devices is still only around 0.1
mm.sup.2/mm.sup.3 due to the poor modulus of the packaging material
(PDMS) requiring even single layer chips to be several mm thick.
This ratio could be significantly improved by packaging these
systems with stiffer polymers. Furthermore, packaging of these
systems in polymers with lower gas permeabilities will help to
eliminate the problems of bubble formation within the channels.
[0170] FIG. 22 illustrates how mechanical valves like those
developed by Thorsen, et al., will be used in dendron extraction.
The array 2200 includes fast acting and leak tight valves 2202
having a low pressure drop and small footprint. Thorsen, et al.,
demonstrated the large-scale integration (LSI) of
pneumatically-actuated microvalves using multi-layer soft
lithography techniques. The pneumatic and hydraulic valves in the
LSI concept by Thorsen, et al., are driven by benchtop compressors
and pumps, which require bulky pneumatic and hydraulic control
channels. Pneumatic actuation of the valves could result in gas
contamination of the reaction stream due to the gas permeability of
the PDMS. In addition, the distribution system for pneumatic
actuation is bulky and not desirable within high component density
applications such as the nanofractory. Electrically-actuated
microvalves capable of being integrated within a nanofractory
architecture can be made by combining a thin film heater with a
material having a large thermal expansion. Paraffin waxes possess a
very large thermal expansion (10-35%) with the potential to deliver
very large pressures (500 Mpa) and have been demonstrated in
surface micromachined and polymer embossing architectures. Other
electrical actuation possibilities include electrostrictive
polymers which would actuate when placed between two static
electrodes. In this way, thin film electrical traces will be used
to replace the pneumatic or hydraulic control networks in Thorsen's
work. PDMS is known to be highly gas permeable, which results in
the evaporation of liquids and the formation of bubbles in
microchannels. Bubbles on the order of 1 mm in diameter have been
observed to form within 24 hours, which, in 100-micron channels,
causes vapor-lock and hinders reactions. This may be handled by
using conformal sealing, which will make the removal of air bubbles
possible. Additional efforts will be needed to package PDMS valves
within stiff, low gas permeable polymers.
[0171] Using the methods described herein, monolithic sorbent
materials have been produced in PDMS microchannels with sufficient
anchoring to yield a useful device for separations. Channel
cross-sections are shown in FIG. 23A-B.
[0172] The porosity of the polymeric stationary phase in monolithic
columns is usually dictated by the nature and amount of the
porogenic solvent employed. Aside from affecting porosity,
adjustments of the amount and nature of the porogenic solvent(s),
alter other properties such as the surface area, nature and
swelling properties of the resulting monoliths. Recently, Chirica
and Remcho described a new synthetic method for preparing monoliths
with porosity dictated by the size of spherical silica particle
templates. In addition to tailoring the pore size, this method
offers the ability to influence the surface characteristics of the
finished polymer by employing silica beads with specific surface
chemistry.
[0173] Dendrimers also can be used to generate uniform pore
structures. Polyamidoamine (PAMAM) dendrimers represent one class
of useful macromolecules. The macromolecules are incorporated into
a solution of functionalized monomers, cross-linker, solvent, and
polymerization initiator. Thermal or photo-initiation of
polymerization, which can be localized in a microscale device by
(1) localized heating with an in-situ micro heater, or (2) by use
of a photomask and exposure to a UV source, results in polymer
production. This is followed by the removal of solvent and
dendrimers, which yields a continuous rod of polymer with uniform
porosity and dendrimer-influenced surface character.
[0174] In one embodiment of this method, azobisisobutyronitrile
(AIBN, 1 wt % with respect to the monomers) was dissolved in a
monomer mixture consisting of 40% ethyleneglycol dimethacrylate
(EDMA), 59.7% butylmethacrylate (BMA) and 0.3% 2-methyl-1-propane
sulfonic acid (AMPS). A porogenic solvent, methanol, was slowly
admixed with the monomers in a 2:3 (v/v) ratio with the goal of
producing interconnecting micropores in the monolith. One ml
aliquots of this mixture were added to several vials containing
specific amounts of Starburst (PAMAM) dendrimer. The dendrimer,
commercially available as a 10% solution in methanol, was used
after the removal of methanol by vacuum distillation. After
addition of the monomer solution, the homogeneous mixtures were
purged with nitrogen for 10 minutes. A fused silica capillary was
filled with the polymerization mixture using a 100 ml syringe. Both
ends of the capillary were sealed with rubber septa, and the column
was submerged in a 60.degree. C. bath for 20 hours. Using a syringe
pump, the resulting monolith was washed with the mobile phase to
flush out the residual reagents, dendrimers and methanol. An SEM
image (cross-section) of the resulting polymer is shown in FIG.
24A-C.
Liquid-Gas Contactor
[0175] Microchannels operatively associated with membranes can be
used for a variety of applications. Another example concerns a
liquid-gas contactor that can be used to facilitate gas absorption
in the liquid. FIG. 25 illustrates one embodiment of liquid-gas
contactor membrane 2500 that can be used to flow a liquid adjacent
one surface of the membrane in a microchannel, and a gas adjacent a
second surface of the membrane in another microchannel. The
liquid/gas contactor membrane 2500 illustrated in FIG. 25 has a
thickness of several hundred microns. This provides ribbing for
stiffening the membrane, which will be positioned between gas and
liquid flowing microchannels. Thin webbing in the bottom, on the
order of 5-10 microns thick, is provided in the membrane 2500. A
laser is used to ablate small apertures (1-2 micron diameter) 2502
in the webbing. Apertures 2502 having a diameter of about 50
microns and a separation distance of about 150 microns are
illustrated in FIG. 25. This allows gas/liquid contact without
breakthrough of the liquid into the gas. Because of the contact,
gas, such as oxygen, can be absorbed into the liquid.
Contactor Membranes in Absorption/Desorption Cycle Micro-Scale Heat
Pumps
[0176] Another potential application of microchannels operatively
associated with membranes is a contactor membrane for use in a
micro-scale heat pump using absorption/desorption cycles. One
embodiment of a heat pump is illustrated in FIG. 32 of the priority
provisional application. FIG. 26 provides a schematic drawing
illustrating the basic components of a heat exchanging system 2600.
The illustrated heat exchanging system 2600 includes heat exchanger
2602, a desorber 2604, an adsorber 2606, a condenser 2608 and an
evaporator 2610. Contactors useful for heat exchanger applications
have a number of desirable physical characteristics, including
having a sufficient stiffness for the application, a thickness of
from about 50 to about 150 microns, a pore size of from about 1 to
about 10 microns, a high break through pressure, which is the
pressure at which solution will pass through the contactor, a high
permeability (mass flux/pressure drop), and a low pressure drop
(the minimum refrigerant vapor pressure for driving the
absorption/desorption process).
[0177] Suitable contactor membranes can be made by laser
micromachining. The method involved first selecting a suitable
material, examples of which include polyimide and polycarbonate. A
membrane was made from such materials by laser micromachining using
a 266 nm Nd:YAG laser. Contactors also can be made by micromolding
the membrane. This involved using a photoresist, such as SU8 2050,
a photomask having appropriate pore sizes, such as a chrome on
glass photomask having 5 micron pores, a substrate, such as a
silicon wafer substrate, and polymeric materials, such as PDMS,
PEG, etc. FIG. 27 schematically illustrates the method for making
the contactor by micromolding techniques.
[0178] FIGS. 28 and 29 illustrate the results obtained by
micromolding contactors. Laser micromachined and micromolded
membranes with straight-through pores have been fabricated
according to the methods described herein. The morphologies of a
engineered straight-through membrane have better permeability then
conventional membranes. The engineered membranes show at least 10
times more mass flux then conventional membranes in a normalized
permeability plot.
[0179] The present invention has been disclosed with reference to
particular embodiments that exemplify the scope of the invention. A
person of ordinary skill in the art will appreciate that the scope
of the invention can vary from that disclosed herein with reference
to these particular embodiments.
* * * * *