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.

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.

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.

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.

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.

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.

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.

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.

Conventional dialysis units are configured as hollow fibers. The membranes are manufactured using spinning technology and generally are about 35μ thick. The membrane is highly porous with the exception of the inner ˜1μ, 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

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.

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.

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.

Microheat exchangers also can be made using the method described herein.

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.

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.

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

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.

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.

FIGS. 2A and 2B schematically illustrates flow mal-distributions that occur on a dialysate side of a conventional fiber-type dialyzer.

FIG. 3 illustrates one embodiment of a microscale dialyzer according to the present invention.

FIGS. 4A-4D are schematic diagrams illustrating one embodiment of a microchannel array having a filter membrane integrally associated therewith.

FIG. 5 is a plan view of one embodiment of a MECS dialyzer according to the present invention.

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.

FIG. 7 is a schematic drawing illustrating a multi-layered dialyzer unit comprising multiple microchannel defining plates and integrally associated polymeric membranes.

FIGS. 8A-8D illustrate plural different diffusion channel design configurations.

FIGS. 9A-9E provide typical dimensions used to make the plates illustrated in FIG. 8.

FIG. 10 is a schematic diagram illustrating one embodiment of an overall dialzyer system according to the present disclosure.

FIG. 11 is a schematic diagram of test device assembled to test microchannel-based fluid filtration.

FIG. 12 is a schematic exploded view of a reactor developed to demonstrate operation of a dialyzer as disclosed herein.

FIG. 13 illustrates different uses for MECS and micrototal analysis systems (OAS).

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.

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.

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.

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.

FIG. 17 is a schematic perspective diagram of one embodiment of an interdigital micromixer.

FIGS. 18A-18B are micrographs of (A) 75 μm thick laser-machined polyimide (200×) and (B) 15 μm thick micromolded PDMS (500×) membranes with 5-8 μm pores on 100 μm spacing.

FIG. 19 is a schematic diagram of an exemplary analytical micromixer with a NSOM (Near-field optical microscopy) ear optical fiber probe.

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.

FIGS. 21A-21B illustrate an alternative modular approach to nanofractory development.

FIG. 22 illustrates using mechanical valves for dendron extraction.

FIGS. 23A-23B are photomicrographs illustrating monolithic sorbent materials produced in PDMS microchannels with sufficient anchoring to yield a useful device for separations.

FIGS. 24A-24C are SEM images of a polymer made using the embodiments of the device described herein.

FIG. 25 is a schematic plan view of a gas-liquid contactor membrane.

FIG. 26 is a schematic drawing illustrating the basic components of a heat exchanging system.

FIG. 27 is a schematic drawing illustrating one embodiment of a method for making a contactor membrane by micromolding techniques.

FIGS. 28-30B illustrate the results obtained by micromolding contactors.

DETAILED DESCRIPTION

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.

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.

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.

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.

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.

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 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.

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, 223rd 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, 62nd, 2427-2431 (2004).

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.

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.

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.

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).

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.

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.

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.

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)].

NCC begins to oxidize in air around 130° 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.

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.

Thus, while NCC has not yet been tested for biocompatibility, prior experience with cellulose in biomedical applications indicates that it will be biocompatible.

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.

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 λD=λ2/D [s], where λ [m] is the characteristic diffusion length (distance between the wall of the fiber and the center of the bulk flow) and D [m2/s] is the diffusion coefficient of the diffusing molecule.

This characteristic diffusion time has to be compared with all other characteristic times (τd—the mean residence time of dialysate, τb—the mean residence time of blood flow through fibers, and τHD—the overall duration of haemodialysis) pertinent to the operation of the conventional dialysis unit. An efficient dialyzer design requires that τD<<τd; τb; τHD.

If the characteristic inter-fiber space 24 in regions with developed shunt flow is of the order of millimeters (10−3 m) than the characteristic diffusion time τD 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 μm the characteristic time τD is about 1 s.

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.

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.

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.

The combination of biocompatibility, stiffness and nanoscale filler dimensions afforded by cellulose nanocrystal-filled PSf allow the incorporation of microscale features (1-100 μm) in the MECS devices.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 CO2 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 μm. The width of the through cut, however, depends on the diameter of the focused beam.

Laminae also have been machined with CO2 laser systems. Most of the commercial CO2 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.

An Nd:YAG pulse laser has been used to cut through, for example, 90-μm-thick steel shims. The line widths for these cuts were approximately 35 μm wide, although with steel, some tapering was observed. For the 90-μm-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 μm. 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.

Laminae also have been patterned using a CO2 laser. For example, a serpentine flexural spring used in a miniature Stirling cooler has been prepared using a CO2 laser. The CO2 through-cuts were approximately 200 μm wide and also exhibited a slight taper. The width of the CO2 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.

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 μm diameter range have been produced.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Typical projections of working embodiment had heights of from about 100 μM to about 200 μm, with diameters of about 125 μm or less. If the projections are shorter than 100 μm, 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.

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.

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.

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° C.).

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.

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.

More specifically, diffusion soldering may involve placing a first strike layer, such as a thin strike layer of nickel (approximately 0.5 μm) 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 μm-10 μm, more typically 2-5 μm 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 μm-10 μm, preferably 2-5 μm thick over the second layer.

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.

The bonding takes place by momentarily raising the stack temperature above the melting point of the low-temperature material (e.g., tin @ 232° 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.

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° C.) bonding process.

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.

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.

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.

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.

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.

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° C. to about 300° 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:HNO3, can be used to eliminate the fixture bridge.

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.

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.

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 μm to about 100 μm. 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 μm to about 1 mm, preferably from about 1 μm to about 500 μm, and even more preferably from about 1 μm to about 100 μm. 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.