WO2006009854A2 - Increase of electrospray throughput using multiplexed microfabricated sources for the scalable generation of monodisperse droplets - Google Patents

Abstract

A compact multiplexed system of electrospraying and a method of fabricating the multiplex system is provided in order to increase by orders of magnitude the liquid flow rate to be dispersed and of retaining the quasi-monodispersity of the generated droplets. The system can be microfabricated as an array of nozzles etched in silicon using a microfabrication technique selected from micro-electro mechanical fabrication techniques and/or micromolding techniques, with a density of 100-2000 sources/cm2. The successful performace of the multiplexed system is critically dependent on a careful selection of the electrode configuration, with entails an extractor electrode mounted at a distance from the nozzle array. The one or more extractor electrodes have the dual function of limiting electric field cross talk between neighboring sources and minimizing space charge feedback from the spray cloud. The system may be optimized to produce uniform droplets simultaneously from all paralleliyed electrosprays, each one operating as an isolated spray in the quasi-monodisperse cone-jet mode.

Description

INCREASE OF ELECTROSPRAY THROUGHPUT USING MULTIPLEXED MICROFABRICATED SOURCES FOR THE SCALABLE GENERATION OF

MONODISPERSE DROPLETS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application No. 60/580,750, filed on June 18, 2004 the subject matter of which is herein incorporated by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR

DEVELOPMENT

This invention was partially made with U.S. Government support from the National Science Foundation (Grant ECS 03-35765), DARPA under Grant No. DAAD19- 01-1-0664, and the U.S. Army under Grant No. W911NF-05-2-0015. Accordingly, the U.S. Government may have certain rights in this invention.

BACKGROUND OF THE INVENTION

Electrostatic means for liquid dispersion in minute droplets are used in a variety of technological applications. In some systems, electric forces exclusively drive liquid dispersion, so that atomization and gas flow processes are relatively uncoupled. Such systems are referred to as electrosprays (ES). Within the electrospray class of atomizers is a particular type characterized by the additional feature of a tight control of the size distribution of the resulting aerosol. Such a system can be implemented by feeding a liquid with sufficient electric conductivity through a small opening, such as the tip of a capillary tube or a suitably treated "hole", maintained at several kilovolts relative to a ground electrode positioned at an appropriate distance from it. The liquid meniscus at the outlet of the capillary takes a conical shape under the action of the electric field, with a thin jet emerging from the cone tip. This jet breaks up further downstream into a spray of fine, charged droplets. Because of the morphology of the liquid meniscus, this regime is labeled as the cone-jet mode. Among the key features distinguishing the cone-jet electrospray from other atomization techniques are: quasi-monodispersity of the droplets; Coulombic repulsion of the charged droplets, which induces spray self-dispersion, prevents droplet coalescence and enhances mixing with a secondary stream; and the use of

{W1365869;2} a spray "nozzle" with a relatively large bore with respect to the size of the generated droplets, minimizing the liquid line obstruction risks.

Electrospray Ionization Mass Spectrometry (ESI-MS), spearheaded by the pioneering work of John B. Fenn at Yale in the 1980's (Fenn et al., "Electrospray

Ionization for Mass Spectrometry of Large Biomolecules," Science, Vol. 246, pp. 64-71

(1989)), is the only practical application of the cone jet electrospray in widespread use, as recognized by his 2002 Chemistry Nobel Prize. Key drawbacks that have hampered applications to other aerosol areas are: first and foremost, the low flow rates at which the cone-jet mode can be established and, to a lesser extent, the restrictions on the liquid physical properties of the liquids that can be dispersed with this technique. If such drawbacks can be addressed and eliminated, the electrospray may find even greater use in a wide variety of applications, well beyond mass spectrometry.

Low flow rates represent a particularly severe drawback for applications requiring that the initial droplet size be small, as, for example, in drug inhalation or nanoparticle synthesis, which are areas of intense aerosol research and development. Since the electrospray exhibits a monotonic dependence of droplet size on flow rate, if small droplets are needed to generate nanoparticles, mass flow rate may be minuscule. Thus, the smaller the desired particle size, the smaller the mass flow rate. Multiplexing the spray source becomes indispensable to generate particles with narrow size distributions at flow rates adequate for various applications. This statement holds regardless of applications, from drug delivery, to the synthesis of nanoparticle ceramics, superconductors, quantum dots, photonic crystals and thin films. If one can tailor the size for a particular effect, for example, for the controlled/targeted drug release or to generate quantum dots with peculiar properties, the impact of fine particle synthesis will be dramatic.

The second drawback limits the applications to particle "precursors" that are well suited to dissolution in conducting fluids. If the goal is to generate very small droplets and ultimately nanoparticles, the conductivity of the working fluids may have to be relatively large, which may conflict with other constraints (e.g., pH-neutral solution in biomedical applications). Furthermore, in some applications organic and non-conductive buffers may be preferable, in which case the cone-jet electrospray would not be viable since its

{W1365869;2} charging mechanism is inductive and requires a finite electric conductivity in the working fluid.

These two drawbacks have relegated the electrospray to the realm of academic curiosity, with the notable exception of mass spectrometry applications. Attempts to remedy the second shortcoming have typically focused on a two-fluid system, in which a working fluid with unsuitable properties is "dragged" by an outer fluid with acceptable electrospray behavior.

With respect to the flow rate limitations, it has been suggested that the total flow rate to be dispersed in small droplets can be increased by multiplexing. This approach has been investigated with conventional machining to a limited degree, in some cases without preserving monodispersity. Multiplexing may also be impractical, by more than one or two orders of magnitude, at least for typical configurations involving capillaries, nozzles or typical protrusions on which sprays are anchored, because the form factor of conventionally machined multiplexed systems limits practical scaling to relatively small amounts. A modestly multiplexed (by a factor of 9), but quite compact, system has been developed by laser etching, as set forth in Tang et al., "Generation of Multiple Electrosprays Using Microfabricated Emitter Arrays for Improved Mass Spectrometric Sensitivity," Anal. Chem., Vol. 73, pp. 1658-1663 (2001), the subject matter of which is herein incorporated by reference in its entirety. However, this system is directed to the improvement of mass-spectrometry sensitivity in electrospray applications, rather than increasing the dispersed flow rates.

The inventors have determined that the task of dramatically increasing the throughput of electrospray systems, without sacrificing droplet monodispersity, may be addressed using microlithographic fabrication techniques developed for the field of MEMS (micro-electro mechanical systems). Namely, by adapting conventional silicon integrated circuit fabrication technology to the machining of mechanical structures in silicon and other materials, there is an opportunity of multiplexing electrospray devices at unparalleled scales, that is, by several orders of magnitude. Efforts using clean room technology in microfabricated electrospray systems have been previously pursued in mass

{W1365869;2} spectrometry, but also in that case the primary goal was to analyze a batch of samples, one at a time, in an automatic way, rather than operating all of them in parallel.

The present application is directed to the electrospray of fluid in the so-called cone-jet mode. Contemplated, is the use of a multiplex system that can produce monodisperse droplets/particles over a wide size range, from a few nanometers to hundreds of micrometers, depending on liquid flow rate, applied voltage and liquid electric conductivity. In particular in the nanometric scale range, the capability of producing monodisperse particles with relative ease is unmatched by any other aerosol generation scheme. The invention is concerned with remedying the main drawback that has hampered to date the widespread use of electrospray techniques in nanoparticle synthesis: low throughput.

The present invention seeks to increase by orders of magnitude the liquid flow rate to be dispersed, while retaining the quasi-monodispersity of the generated droplets. Contrary to the operation of a single electrospray that is rather forgiving with respect to the electrode geometry, successful performance of the multiplexed system is shown to be critically dependent on a careful selection of the electrode configuration as well as the precise positioning of individual electrospraying spray sources in the multiplex system.

Bocanegra et al., J. Aerosol Sci. (2005), the subject matter of which is herein incorporated by reference in its entirety, demonstrated the use of a type of multiplex system that anchored a multiplexed cone-jet on holes drilled in materials that were not wetted by the liquid to be dispersed and dispensed with nozzles, capillaries or any kind of protrusions. Using CNC fabrication, Bocanegra et al. reported a respectable multiplexing density of 115 emitters/cm², which is believed to be the limit achievable with that technique. However, greater multiplexing densities are still required in order to achieve adequate throughput.

The inventors of the present invention have developed an improved multiplex system fabricated using microfabrication techniques, including MEMS, micromolding, and combinations of the foregoing, that can be used with any electrosprayable fluid. Furthermore, the microfabrication techniques usable in the present invention are batch

{W1365869;2} processing methods, which offer unique economies of scale as manufacturing methods. MEMS fabrication techniques are well known in the art and widely used, as described, for example, in U.S. Patent No. 6,861,363 to Harchanko et al. and U.S. Patent No. 6,824,697 to Moon et al., the subject matter of each of which is herein incorporated by reference in its entirety. In addition, it is also possible to simplify the fabrication by using a micromachined silicon master as a mold for the construction of distributors in other materials. Micromolding from microfabricated silicon masters can be used for high fidelity fabrication in elastomers as well as other polymers and ceramics. Micromolding techniques are also well known in the art as described, for example, in U.S. Patent Application Publication No. 2005/0067286 to Ahn et al., U.S. Patent No. 6,899,838 to Lastovich, and U.S. Patent No. 6,780,353 to Billiet et al., the subject matter of each of which is herein incorporated by reference in its entirety.

The present invention provides a parallelized electrospray dispersion system that increases by orders of magnitude the liquid flow rate to be dispersed, while retaining the quasi-monodispersity of the generated droplets.

Small-scale combustion applications for liquid-fueled batteries are one example of an application that would benefit from the use of the multiplex system of the invention. Other applications may include nanoparticle synthesis, in which the electrospray capability of tight control in size distribution has already been demonstrated. Examples include nanoparticle synthesis of biomaterials, high temperature synthesis by electrospray pyrolysis of ceramic oxides, quantum dots and metal oxides, electrospray coating techniques and nanofiber synthesis by electrospinning.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an improved multiplex system and a microfabrication technique for making a multiplex system that is capable of electrospraying monodisperse fluid droplets.

It is another object of the present invention to provide an improved multiplex system and a microfabrication technique that is capable of producing a large flow rate of fluid droplet for a given droplet size.

{W1365869;2> It is yet another object of the present invention to provide suitable criteria for the design of optimal electrode configurations.

It is yet another object of the present invention to provide an improved multiplex system that includes one or more extractor electrodes arrays, the first of which is mounted at a short distance from the nozzle array, as part of the electrode system. The one or more extractor electrodes arrays have the dual function of limiting electric field cross talk between neighboring sources and minimizing space charge feedback from the spray cloud.

It is yet another object of the present invention to provide the ability to independently control the voltage of individual extractor electrodes or groups of extractor electrodes to adjust the spray pattern of the electrosprayed fluid in the multiplex system of the invention.

It is another object of the present invention to provide a method of fabricating the improved multiplex system of the invention such that the spacing, diameter, and height of each nozzle of the nozzle array may be precisely controlled.

To that end, the present invention is directed to a microfabricated multiplex system for electrospraying monodisperse fluid droplets. The system of the invention typically comprises: a) a distribution plate formed using a fabrication technique selected from the group consisting of micro-electro mechanical fabrication, micromolding, and combinations of the foregoing, to create an integral array of substantially uniform nozzles in^" the distribution plate, wherein the nozzles protrude to a selected height from a surface of the distribution plate; b) at least one extractor electrode array positionable at a distance from the top of the array of protruding nozzles; c) at least one insulating spacer arranged between the distribution plate and at least one the extractor electrode array to position the at least one extractor electrode array at the desired distance from the top of the array of protruding nozzles;

{W1365869;2} d) a source of fluid operably connected to the distribution plate for providing the fluid to be electrosprayed; and e) electrical means for maintaining a desired voltage drop between the distribution plate and the at least one extractor electrode array.

The invention is also directed to an improved method of fabricating the multiplexing system comprising the steps of: a) fabricating a distribution plate using a fabrication technique selected from the group consisting of micro-electro mechanical fabrication, micromolding, and combinations of the foregoing, to create an integral array of substantially uniform nozzles in a surface of the distribution plate, wherein the nozzles protrude to a selected height from the surface of the distribution plate; b) positioning at least one extractor electrode array at a distance from the top of the array of protruding nozzles; c) arranging at least one insulating spacer between the distribution plate and the extractor electrode array to position the at least one extractor electrode array at the desired distance from the top of the array of protruding nozzles; d) connecting the distribution plate to a source of the fluid to be electrosprayed; and e) providing an electrical connection to maintain a desired voltage drop between the distribution plate and the at least one extractor electrode array.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a system schematic with fluid control volume.

Fig. 2 demonstrates the microfabrication process flow used to fabricate the tested devices.

Fig. 3 depicts a typical 91 -nozzle system, with scanning electron micrographs of the nozzle array and of an individual nozzle.

Fig. 4 is a schematic of various electrode configurations, with Fig. 4A depicting the extractor electrode in accordance with the present invention, Fig. 4B depicting a simple flat electrode, and Fig. 4C depicting a ground electrode shaped as a paraboloid.

{W1365₈69;2} Fig. 5 is a comparison of the electric field at the outer nozzle and at the central one in a system of 7 nozzles for the three electrode geometries in Fig. 3.

Fig. 6A depicts a microfabricated distributor of the invention, with the penny as size standard, and Fig 6B demonstrates the system in operation with a multitude of sprays.

Fig. 7 shows the average droplet diameter in individual cone-jet electrosprays in the multiplexed mode.

Fig. 8 depicts a typical "firing" pattern of the extractor electrode system as the flow rate is either increased (top) or decreased (bottom). The dots are due to the scattering from each spray droplets off a He-Ne laser sheet parallel to the distributor. The dot pattern is duplicated via reflection from the shiny metal extractor electrode surface, as faintly visible on the left of each image.

Fig 9. demonstrates the hysteresis in the "firing" pattern as the liquid flow rate is first increased and then decreased.

Fig. 10. presents details of the electric field computed on each of the nozzles in a 19-nozzle hexagonal pattern. Numbering correspond to different positions of the nozzles, as shown in the inset.

Fig. 11 shows the average droplet diameter in individual cone-jet electrosprays in the multiplexed mode with the outer "ring" of plugged "dummy" nozzles.

Fig. 12. depicts the average current per jet versus average flow rate per jet for a multiplexed and single cone-jet ethanol electrosprays.

Fig. 13 depicts a system schematic in which multiplex system is used for the coflόw of two liquids, the outer of which is electrosprayable.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to an improved microfabricated multiplex system for electrospraying monodisperse fluid droplets. The multiplex system of the invention is

{W1365869;2} capable of producing a large flowrate for a given droplet size, which was previously unattainable in the prior art.

The improved multiplex system of the invention comprises a distribution plate comprising an array of substantially uniform nozzles integrally formed in the distribution plate. The distribution plate is fabricated using microfabrication techniques selected from the group consisting of micro-electro mechanical fabrication, micromolding, and combinations of the foregoing, to create the array of substantially uniform nozzles in a surface of the distribution plate.

Preferably, the nozzles protrude to a selected height from a surface of the distribution plate. Li one embodiment, the nozzles are flush with the distribution plate (e.g., the protrusion is practically zero), while in other embodiments the nozzles protrude to various heights above the surface of the distribution plate. In some applications it is desired that the nozzles protrude to a height of at least about 50 microns. In other applications, it is desired that the nozzles protrude to a height of less than about 50 microns. A suitable height of the nozzle protrusions would be readily ascertainable to one skilled in the art, depending on the nozzle density, nozzle configuration, electrode geometry, fluid being electrosprayed, flowrate, etc.

The multiplex system also comprises at least one extractor electrode array positionable at a distance from the top of the array of nozzles. Depending on the application, the extractor electrode array can be a single extractor electrode that may or may not have different applied voltages at different electrodes, or, in addition to the first electrode, multiple stacked electrode plates can be critically positioned to control the spray flow. The design of the extractor electrode array again depends on various factors, such as current, droplet size, flow rate and fluid being electrosprayed, which would be well known to a person skilled in the art. The at least one extractor electrode array comprises a plurality of holes, each of which is alignable with a corresponding nozzle in the nozzle array. The plurality of holes in the at least one extractor electrode array are comparable in diameter with the outside diameter of each of the nozzles of the nozzle array. In one preferred embodiment, the at least one extractor electrode array comprises a uniform conducting material. One suitable material is stainless steel, although other materials

{W1365869;2} would also be known to those skilled in the art. In another embodiment, the extractor electrode array comprises an insulating material with metal electrodes contained therein. For example, the at least one extractor electrode array may comprise an insulating quartz plate with corresponding holes therein and individual or grouped patterned metal electrodes, wherein the metallic electrodes comprise gold with a thin adhesion layer of chrome or titanium thereon. The at least one extractor electrode array may also comprise electrodes that are capable of applying different voltage to an individual nozzle or group of nozzles

The at least one extractor electrode array is preferably planar and is positioned near the top of the nozzle array. In one embodiment, the at least one extractor electrode array is positioned at a distance of about 200-500 microns downstream from the top of nozzle array. In another embodiment, the at least one extractor electrode array may be positioned upstream of the nozzle array. Other configurations of the at least one extractor electrode array and the nozzle array would also be apparent to one skilled in the art.

If desired, the multiplex system of the invention may comprise alignment pins and corresponding alignment holes to align the nozzle array with the at least one extractor electrode array.

Typically, at least one insulating spacer is arranged between the distribution plate and the at least one extractor electrode array to position the at least one extractor electrode array at the desired distance from the top of the array of protruding nozzles. The at least one insulating spacer may be formed from a variety of materials, including, but not limited to, glass, ceramics, and other dielectric materials.

A source of fluid is connected to the distribution plate for providing the fluid to be electrosprayed. Several non-limiting examples of the electrosprayable fluid include solutions of biomaterials, ceramic oxides, quantum dots, coatings, and combinations of the foregoing or their precursors. In one embodiment, the source of fluid is a fluid reservoir, and the nozzle array is attached to the fluid reservoir with a suitable bonding agent, which is typically non-soluble in the electrosprayed fluid.

{W1365869;2} The at least one extractor electrode array, at least one insulating spacer, and distribution plate are joined together using a suitable bonding agent. The bonding agent may be selected from epoxies, liquid copper, ceramics, polymeric materials, elastomers, acrylic resins, including cyanoacrylates and combinations of the foregoing depending on applications. Other bonding agents would also be readily apparent to one skilled in the art. In another embodiment, the at least one extractor electrode array, at least one insulating spacer, and distribution plate are joined together using anodic bonding.

Finally, electrical means are provided for maintaining a desired voltage drop between the distribution plate and the at least one extractor electrode array. Such electrical means typically include one or more external high voltage power supplies and suitable conduction paths to the electrodes, such as insulated metal wires, as would be apparent to one skilled in the art.

The distribution plate of the invention is most preferably formed using micro- electro mechanical fabrication techniques (MEMS) or micromolding techniques. In the case of micromolding, the distribution plate is cast from a micromachined master. Optionally, one or more intermediate molds may be prepared such that the distribution plate is cast from the one or more intermediate molds. Other fabrication methods such as ultrasonic drilling etc, are also possible depending on the desired feature sizes of the distribution array. As discussed above, MEMS techniques describe a group of microfabrication techniques based on microlithographic fabrication.

In one embodiment of the invention, the density of the nozzles formed in the distribution plate is between about 100-2000 nozzles/cm². However, the density of the nozzles is not limited to this range and other nozzle densities (both larger and smaller) are contemplated by and usable in the practice of the invention. The nozzle density may be higher, for example, if space charge of the electrospray droplet cloud is not an issue. Also, if smaller diameter nozzles are used, the nozzle density may be higher. The nozzles may be arranged in various geometric patterns. For example, the nozzles may be arranged in a hexagonal pattern, which leads to the densest packing. In another embodiment of the invention, nozzles may be clustered or arranged in groups specific to a specific application.

{W1365869;2} The multiplex system of the invention is optimally constructed such that the spacing, diameter, and height of each nozzle in the nozzle array is precisely controlled. The reproducibility of geometric features among protrusions is an important prerequisite to equidistribution of flow rates among the multiplexed nozzles, and to the establishment of a controlled electric field at each nozzle. Under these conditions, it is critical that the spacing of the nozzles and the inner and outer diameters of the nozzle be fabricated to a strict tolerance. For example, using microlithographic based MEMS fabrication techniques the lateral accuracy of the position of the nozzles in the nozzle array may be less than about 100 nm. hi addition, for certain nozzle heights, densities and inner diameters, the tolerance of the outer diameter of each nozzle of the nozzle array may be less than about 1 micron, and the tolerance of the inner diameter of each nozzle of the nozzle array may be less than about 0.5 micron, or in some cases less than about 0.3 micron. It is noted that these tolerances are provided only as examples, and one skilled in the art would be able to construct a suitable multiplex system to other tolerances, depending on the desired application.

In one embodiment, substantially all of the nozzles of the nozzle array operate simultaneously at approximately the same flowrate. In other embodiments of the invention, it may be desired to turn on/off individual nozzles or groups of nozzles in the nozzle array to adjust the spray pattern of the electrosprayed fluid. Turning on or off individual nozzles or groups of nozzles may be achieved via a variety of means including but not exclusively adjusting the extractor electrode voltage or voltages, and/or modifying the pressure to the liquid in the distribution plate or even in individual nozzles or groups of nozzles. This may be desirable, for example, in applications where precise effectively binary control of flow rate at the precise level of an individual electrospray is desired.

The invention is also directed to a method of fabricating a multiplexing system comprising the steps of: a) fabricating a distribution plate using a fabrication technique selected from the group consisting of micro-electro mechanical fabrication, micromolding, and combinations of the foregoing to create an integral array of substantially uniform nozzles

{W1365869;2} in a surface of the distribution plate, wherein the nozzles protrude to a selected height from the surface of the distribution plate; b) positioning at least one extractor electrode array at a distance from the top of the array of protruding nozzles; c) arranging at least one insulating spacer between the distribution plate and the at least one extractor electrode array to position the at least one extractor electrode array at the desired distance from the top of the array of protruding nozzles; d) connecting the distribution plate to a source of the fluid to be electrosprayed; and e) providing one or more electrical connections to maintain desired voltage drops between the distribution plate and the at least one extractor electrode array.

In one embodiment, the distribution plate is fabricated using well-known micro- electro mechanical (MEMS) fabrication techniques, comprising the steps of a) providing a silicon wafer with a silicon oxide mask layer preferably on both sides; and b) patterning the silicon wafer to produce the protruding nozzle array in the desired pattern in the silicon wafer using a resist material followed by a suitable etchant. Typical resists include U.V. resists and other laser imageable organic photoresists. Figure 2 provides a schematic of a suitable microfabrication process flow for the present invention. The means for patterning the silicon wafer may be selected from techniques selected such as deep reactive ion etching, wet anisotropic etching, directed etching, wet etching, ion milling and combination of the foregoing. In a preferred embodiment, the silicon wafer is patterned using deep reactive ion etching.

- In another embodiment, the distribution plate is fabricated using micromolding fabrication techniques from a micromachined master. This master may be fabricated via MEMS techniques or other methods. The micromolding process typically comprises the steps of a) preparing a micromachined master of the distribution plate using silicon via MEMS fabrication methods; and b) casting the distribution plate from the micromachined master. The micromolding process may further utilize one or more intermediate molds that are prepared from the micromachined master. In the micromolding process, the distributor plate may be cast from a variety of materials, including, but not limited to elastomers, acrylics, glass, green ceramics, hard ceramics, silicon carbide, and combinations of the one

{W1365869;2} or more of the foregoing.

The at least one extractor electrode array is typically microfabricated using photolithography and etching to provide a plurality of holes that are each alignable with a corresponding nozzle in the nozzle array of the distribution plate as is well known in the art. The plurality of holes in the at least one extractor electrode array are preferably comparable in diameter with the outside diameter of each of the nozzles of the nozzle array.

In one embodiment of the invention, the multiplex system is fabricated such that that

wherein L is the distance from the top of the nozzle protrusion in the nozzle array to the at least one extractor electrode array, h is the height of the nozzle protrusion of each of the nozzles in the nozzle array, and Ij_n is the distance between each of the nozzles of the nozzle array as measured from a centerpoint of each nozzle. It is noted that this is only one suitable example of the configuration of the system and other systems could also be designed, depending on the desired application, as further elaborated below.

The multiplex system may be designed such that the average droplet size of the electrosprayed droplets exiting each nozzle has a relative standard deviation (ratio of diameter standard deviation and mean diameter) of less than about 0.1. The relative standard deviation may be different depending on the operating parameters of the multiplex system and the desired application. A person skilled in the art could design a suitable system with a desired relative standard deviation.

A successful design of the multiplex system of the invention ensures that all of the nozzles can operate simultaneously for a broad range of flow rates, with uniform droplet size from nozzle to nozzle, in a compact multiplexed system. In view of the monotonic dependence of droplet size on flow rate, once the cone-jet regime is established, uniformity of droplet size for all nozzles imposes uniformity of flow rates. An optimal

{W1365869;2} design ensures fabrication simplicity and nearly identical conditions for all nozzles. Although fine tuning conditions in each nozzle, with independent control of flow rate and electric conditions, would pose significant fabrication and operational challenges, it may be desired in some applications that nozzle array be controlled so that individual nozzles of the nozzle array can be turned on/off to achieve optimal results. What is most critical to the success of the present invention is the ability to precisely control the operation of the nozzles to achieve the desired result.

It is also within the scope of the present invention to use the multiplex system of the invention for the coflow of two liquid streams. The general prerequisite for electrospray dispersion is that the liquid (solution) is well suited for the task, with the liquid electric conductivity being the key variable affecting elctrosprayability. Examples of suitable liquids include alcohols, water, and hydrocarbons with conductivity-enhancing additives. In instances in which the liquid does not have the right physical properties for proper electrospray behavior, the electrospray of two coflow liquid streams can be implemented, the outer of which, having the "right" properties, would drag the inner stream. If the two streams are immiscible, this approach could also be used to synthesize nanoshells. To obtain the cone-jet, electrodynamic shear stresses are established, so that the liquid meniscus is pulled into a very fine filament. This does not require that the bulk of the fluid be conductive. So, it may be sufficient to ensure that a suitable distributor of surface charge be available as part of the atomizer unit, while, in principle, a nonconducting liquid can be used in the bulk. In the case of the two fluid streams, the microfabrication approach also appears to be feasible. Figure 13 shows how microfabrication could be adapted to the two-liquid electrospray system, which would require the same flow process described above and the registration of two microfabricated distributors with slightly different geometric features. According to Fig. 13, Fluid 2 would be electrosprayable, whereas Fluid 1 with poor electrospraying characteristics would contain the materials of interest in the intended applications. In some cases the presence of the conducting outer layer in the droplets may be undesirable because of contamination issues. However, the subsequent evaporation may avoid this complication, especially in the case of volatile alcohols. From a fundamental viewpoint, the feasibility of the technique relies on the relative magnitude of the dissolution characteristic time for the two coaxial liquids, the residence time in the cone-jet, and the evaporation time.

{W1365869;2} Various factors were considered in designing an optimal multiplex system in accordance with the present invention. First, a criterion was formalized by considering the system sketched in Figure 1, highlighting a common feed tube, a reservoir with an optional flow homogenizer, the parallel nozzles and the cone-jet liquid/air interface. If we apply a momentum balance to the generic control volume CVj, under steady state conditions and with negligible body forces, we obtain l vpv - dA = ∑K

CS₁ where the term on the right hand side combines all surface forces acting on the control surface CS; bounding CVi. If each parallel channel is to have the same flow rate, the inertia term on the left hand side of the equation must be the same, regardless of the channel. The equidistribution of flow rates then implies that for the generic channels i and j

∑F_Sι = ∑F_Sj =∑F_s =F_Sr +F_S2 +F_S3 ,

where subscript i and j can be dropped, and the last equality refers to the decomposition of the total surface forces in each channel into three contributions: F_s , F_s and F_s , referring to the homogenizer region, the nozzle and the cone-jet interface, respectively, hi region 1, only pressure and viscous forces are at play with the establishment of a pressure drop to overcome viscous losses, hi region 2, similar considerations apply, with the establishment of the well-known Hagen-Poiseille flow at the prevailing Reynolds numbers of unity order. Li region 3, capillary forces and electrohydrodynamic normal and shear stresses at the liquid/air interface are important and would need to be integrated on the liquid/air interface. Capillary forces depend on the liquid surface tension and on the interface geometry. Electrohydrodynamic stresses depend on the electric field at the nozzle outlet. Implicit in this argument is that the electric charge has relaxed to the fluid/air interface, as typical of the stable cone-jet electrospray regime.

In region 1, uniformity of the pressure drop across the homogenizer would be required with the insertion of baffles, honeycombs, beads, frits and other obstructions that

{W1365869;2} would ensure that there are no preferential paths from the feed tube outlet to each nozzle. However, if F- »K , there would not even be need for a homogenizer since the prevailing Reynolds number in the fluid reservoir is of order 10^"2 and one would instead expect a uniform Stokes regime, with no separation at the walls and F_s « 0. The condition F_S2 » F^ can be reached by judicious selection of the inner diameter of the parallel nozzles and flow uniformity from nozzle to nozzle would be guaranteed by the high spatial resolution of microfabrication. With either F_s or F_s or both much larger than F_s , the system should be relatively uninfluenced by edge effects in the electric field distribution affecting F₈ (see Fig. 5) and the requirement on the electric field is that it be sufficiently intense for the cone-jet to be established at each nozzle.

If neither of the conditions above is fulfilled, the following situation ensues. For a given interface geometry and liquid surface tension, capillary forces are fixed. Particularly important now become the electrohydrodynamic stresses that extrude the fluid into a ligament that is orders of magnitude smaller than the nozzle bore. In such a case, great care must be taken to ensure that the electric field does not vary significantly from nozzle to nozzle, since this field controls not only the establishment of the cone-jet regime, but also the liquid flow rate that is drawn from each nozzle.

To establish an intense electric field, the simplest configuration would entail mounting a flat electrode at a distance from the multiplexed distributor. Critical is the distance selection, since a few characteristic length scales are already apparent in the distributor design: the inter-nozzle distance, /;„, the nozzle protrusion, h and the nozzle diameter, D. Microfabrication allows for the manufacturing of essentially planar structures, with protrusions limited by the wafer thickness. If the flat electrode is mounted at a distance L» h, the effect of the protrusion would be irrelevant and the electric field established would essentially be that which is between two capacitor plates. It is doubtful that with such a configuration sufficiently intense electric fields can be established for the cone-jet mode of operation, before the onset of corona breakdown in the surrounding gas. Furthermore, feedback from space charge may become inevitable. If, on the other hand, L~h« U_n, the effect of the protrusions will be significant and the field can be localized with minimal influence of the neighboring nozzles. Inevitable flooding of the liquid

{W1365869;2} flowing through the system would prevent operation with a ground electrode a fraction of a millimeter away from the nozzle.

If instead a ring electrode to let the fluid through a small opening is used (e.g., the extractor electrode of the invention), the cone-jet can be established and a spray with the right "quality" can be formed. This configuration, often called "extractor electrode" is typically used in electron beam applications. It was also used in early electrospray applications for electric propulsion and combustion. The generated droplets would eventually reverse their paths and be attracted back to the lower potential electrode, causing flooding and eventual interruption of the flow. This effect can be avoided if an additional electrode is put in place at an even lower potential to "sweep" the droplets away and use them for the intended applications. This can be combined also with an external flow that would drag the droplet away overcoming electrostatic attractive forces. The additional advantage of this configuration is that it shields the cone-jet region at the source of the spray from the region where the spray cloud disperses, with attending space charge. A separation of the cone-jet region from the spray utilization region is generally desirable for stability and application considerations.

The typical dependence of the current emitted by the electrospray on the liquid flow rate is according to a power law of exponent α. If the electrospray is now partitioned uniformly into a plurality of electrosprays, n, each following the same power law, then

where Q is the total liquid flow rate, and Q₁ is the flow rate through the z-cone-jet.

The implication of the above equation is that if the application requires the highest possible charging of the liquid, as for example in ESI-MS, the multiplexed mode will yield a current gain by a factor n^l~a in the current passed through the spray, where α is invariably less than unity and typically close to 0.5. Consequently, at a constant flow rate, we anticipate that the current monotonically increases with the number of jets and the multiplexing level.

{W1365869;2} Example:

Multiplexed electrospray distributors fabricated in accordance with the present invention were microfabricated in silicon using Deep Reactive Ion Etch (DRIE) of silicon wafers. Uniform nozzles, interspaced at various distances (2.52mm, 1.26mm, and 0.675mm), and protruding from 150μm to 450μm were patterned with outer diameters ranging from 180μm to 240μm, and a fixed inner diameter of 120μm. Figure 2 sketches the specific microfabrication process flow used to fabricate the devices produced in accordance with the parameters of the example.

Using double-sided wafer processing and deep reactive ion etching, a double side polished Si wafer with an oxide mask layer is patterned on both sides to realize nozzle arrays. DRIE of silicon can yield essentially straight sidewalls with large aspect ratios. Minimum feature sizes for the sizes of the fabricated devices can be on the order of one micron, which guarantees virtually identical protrusions, all acting as pseudo-capillaries. Figure 3 shows scanning electron micrographs (SEMs) of a typical configuration, in this case a 91 nozzle hexagonally patterned arrangement. Excellent pattern transfer is evident on the individual nozzle SEM, with nearly vertical sidewalls in both the nozzle interior and exterior. The process allows for easy variation (e.g., nozzle scaling and array design) to optimize the intended application.

A typical arrangement requires mounting the microfabricated distributor on a liquid reservoir, positioning suitable additional electrodes, and providing an electric connection to maintain the desired voltage drop between the distributor and the other electrodes. Details on the optimal electrode configuration are provided below. A multiplexed system of approximately 250 nozzles/cm² was used, although, as discussed above, higher and lower density multiplexed systems may be readily microfabricated in the same manner.

The current was measured by connecting the virtual ground to a voltmeter with known input impedance. Visual observation of the mode of operation was made possible by a laser beam focused by two lenses into a sheet parallel to the distributor surface and positioned a few millimeters downstream of the cone-jets. Scattering of the charged

{W1365869;2} droplets in each spray resulted in the visualization of individual spray cross sections appearing as small circular spots.

Tests were performed using ethanol, an alcohol with good electrospraying properties. The liquid was pumped continuously into the reservoir using a syringe pump with different syringe sizes to ensure that the plunger would be displaced at a reproducible and accurate speed. At the low flow rates, small (0.25 ml and 1 ml) syringes were used; the smaller the diameter of the syringe, the more accurate and steady the motion of the syringe plunger. As a result, the measurement of the current was more accurate and the range of stable flow rates for a given mode was increased. The liquid was sonicated for a few minutes prior to being loaded in the syringe slowly and steadily, to minimize the formation of microbubbles. Subsequently, the loaded syringe was sonicated for a few minutes to further eliminate possible microbubbles.

Droplet sizes were measured by a Phase Doppler Anemometer (DANTEC,

Electronik) capable of measuring simultaneously droplet size and two velocity components from the scattering of a frequency-modulated Argon Ion laser beam (Spectra Physics). The electrospray set-up was mounted on a multi-direction translational stage allowing for the systematic scanning of the spray by the laser probe volume. This volume was imaged on the receiver optics, which was coupled to photomultipliers for the signal recording and subsequent processing. A dedicated electronic processor sampled and analysed the signal using Dantek BSA Flow Software. For each measurement, 5000 counts per sample were taken. Measurements were performed at a given flow rate by selecting the applied voltage so that the size distribution histogram would be as monodisperse as possible. In the cone-jet mode, although the bulk of the flow rate is dispersed in uniform size droplets, a small percentage may be dispersed as much smaller satellites that are electrostatically and inertially confined to the periphery of the spray. To ensure that primary droplets were sized up, the laser probe volume was positioned along the axis of each spray.

The chosen electrode configuration is depicted in the schematic in Fig. 4A. As discussed earlier, critical is the distance selection, since a few characteristic length scales are already apparent in the distributor design: the inter-nozzle distance, /,„, the nozzle

{W1365869;2} protrusion, h and the nozzle diameter, D. In this example, h was limited to 0.45 mm, which for the densest packing is of the same order as the inter-nozzle distance, /,•„, at 0.675 mm. The microfabricated Si distributor is charged at about IKV potential above that of a metal ring extractor plate positioned at a distance of typically 200-500 μm by means of a glass insulator spacer, under conditions in which L<h< h_n. Since L is at most a factor of 3 smaller than l_in, it is likely that nozzle cross talk may not be completely eliminated. The stainless steel ring extractor itself was designed and microfabricated using photolithography and metal etching to tolerances compatible with the microfabricated nozzle array. Also visible in the schematic is a ground electrode several millimeters downstream.

Modeling of the external electric field using multiphysics modeling (FEMLAB, available from COMSOL Inc.) provided supporting evidence of the electric field design criterion. Since the presence of the liquid and its coupling with the electric field is unaccounted for and poses a much more challenging problem, these calculations are qualitative in nature.

Simple electrostatic modeling is revealing in explaining some of the experimental observations. To that end, solutions of the Laplace equation Aφ = 0 for the electric potential φ were computed using FEMLAB for a simplified geometry consisting of 7 nozzles protruding from a distributor plate. The electric field was computed by post¬ processing the potential field. Computations were performed for three cases: the extractor electrode of the invention (Figure 4A); a simple flat electrode at a working distance of 1 cm from the wafer (Figure 4B); and a ground electrode shaped as a paraboloid to decrease the distance between the innermost nozzles and the ground, as compared to that of the outermost nozzles (Figure 4C). The voltage levels in the three cases were chosen so that the electric fields at the nozzles would be comparable in the three cases, hi the second case the wafer was charged at 28 KV with respect to a flat ground electrode 1 cm away; in the third one, it was charged at 8 KV with respect to an hemispherical ground electrode, the bottom of which was 3 mm away from the wafer. Figure 5 shows the electric field at the three nozzles where the cone-jet would be formed.

{W1365869;2} In the second case (Figure 4B), to achieve approximately the same field, one needs extremely high voltages. In a typical startup procedure, the outer nozzles in the array would electrospray first, as a consequence of the more intense field locally, whereas the innermost nozzles would fail to operate leading to flooding of the distributor with the formation of a liquid layer that could not be disrupted into controlled and properly anchored electrosprays. Increasing the voltage to the extremely high values used in the calculations would not be practical. Sharp corners in contact with the charged electrode, contact wires, or even surface irregularities resulting from microfabrication can cause corona discharge in the surrounding gas. This configuration failed to work in preliminary attempts.

In the third case (Figure 4C), in which the ground electrode was properly shaped to enhance the homogeneity in electric field among the nozzles and reduce the applied potential to approximately 8 KV, we managed to get all sprays to "fire" at the same time. With the ring extractor and the paraboloid ground configurations the degree of nonuniformity in the field between the side nozzles and the central one is reduced from 22% in the case of the flat electrode (Fig. 4B), to approximately 10%, which may explain why these configurations were successful. However, the paraboloid geometry proved impractical since operation could be established for brief periods of time before electrode flooding would ensue. Furthermore, the geometry of the ground electrode may have to be tailored to a particular liquid flow rate and liquid conductivity, since both variables may affect the space charge field.

The electric field comparison in Fig. 5 demonstrates the desirability of the ring extractor electrode of the invention. Figures 6A and 6B show pictures of the microfabricated distributor, with a customary penny as size standard, and of the system in operation with a multitude of sprays issuing from the system.

Next, the critical role of the external electric field, when K « 0, K ≤ F^ , was examined. In such a case, there is no homogenizer and the pressure drop in the nozzles does not overwhelm interfacial forces, electrohydrodynamic stresses that depend on the electric field at the nozzle are particularly important since this field controls not only the establishment of the cone-jet regime, but also the liquid flow rate that is drawn from each

{W1365869;2} nozzle. The electric field is due to the electric potential applied between electrodes, the so- called external field, and can be mitigated by the space charge field that is due to the charged droplet cloud downstream, if the extractor electrode is inadequate to shield the cone-jet from the cloud. In the present experiments characterized by liquids of relatively modest conductivity, space charge does not appear to be an issue. Its feedback may become non-negligible as the current through the system increases and at some point it may even hinder the system operation.

As long as the external electric field is the same at each nozzle, the goal of uniform flow rates and droplet size can be achieved. However, the calculations discussed in Figure

5 show that edge effects may be inevitable, with the electrostatic pull in the outermost array of nozzles being stronger, which should result in larger flow rates and droplet size.

This nonuniformity was confirmed by indirect experimentation. To ease the monitoring of the system, the outermost nozzles were cut to leave and hexagonal pattern of 37 nozzles. Figure 7 shows the droplet average diameter measured in a scan across the hexagon with nozzle numbers identified in the inset in the figure. As anticipated, the outermost nozzles pass a higher flow rate and generate larger droplets, which is entirely consistent with the external field electrostatic pattern in Figure 5.

Further evidence of the importance of the external field uniformity, under conditions of F_Sι * 0 and F₅₂ < F_Sj , is provided by the "firing" pattern of the multiplexed system as the flow rate is increased. Figure 8 shows the scattering pattern observed as a laser sheet is shone parallel to the distributor surface. The top row of pictures shows the pattern obtained as the flow rate is increased at a fixed voltage difference between distributor and the extractor ring. The bottom row pertains to the pattern obtained as the flow rate is decreased. Also in this case experiments were conducted with arrays of either two or three hexagonally configured and concentric nozzles, obtained from the initial distributor by selectively cutting the outermost nozzles. The pattern in each picture is mirrored by the reflection on the shiny metal extractor electrode surface on the left of each image. It is observed that, as a function of flow rate, the outermost nozzles at the vertices of the hexagon begin to first fire (top left). As the flow rate is increased, the other nozzles in the outer most "ring" gradually turned on. Next, the central nozzle begins to fire and finally the intermediate "ring" is turned on, until all 19 nozzles are "firing" at the same

{W1365869;2} time. Most interesting is the hysteretic pattern with respect to the number of jets that are simultaneously operating, which is a function of whether a particular flow rate is achieved by decreasing or increasing the liquid pumped through the system. As shown in Figure 9 for the system of 19 electrosprays, there is a monotonic dependence of number of jets operating on flow rate as the flow rate is increased. Once all jets have been turned on, the flow rate can be decreased by more than a factor of two before any electrospray disappears, hi other words, the average flow rate needed to generate a new spray at a nozzle is higher than the average flow rate to keep a spray. Furthermore, when a mechanical and/or electrical perturbation is introduced (for example by tapping the fluid reservoir, or introducing a metal tip in the vicinity of non-operating nozzles), more cone- jets can be turned on (as compared to the data in Figure 9).

Figure 10 shows details of the electric field computed on each of the nozzles in the 19-nozzle hexagonal pattern, with numbering of different profiles in correspondence of different nozzle types (e.g. at a vertex of the hexagon, at the center, etc.) The "firing" pattern in Fig. 8 (top row) for increasing flow rate is entirely consistent what the hierarchy of intensity of electric field at the nozzle outlets. This observation suggests that first space charge is not controlling the system perfonnance, as intended by the selection of the extractor electrode design. Second, it shows that details of the cone-jet morphology and of the potential drop through the quasi-equipotential liquid are not critical. If this is the case, further fine-tuning of the microfabrication design, which may be examined by using FEMLAB and solving Laplace equation for different geometries can yield greater uniformity in both firing pattern and droplet size.

We also notice that the greatest nonuniformity in the field is between the outermost

"ring" and the rest of the nozzles. If such nozzles are plugged, greater droplet uniformity would ensue at the cost of sacrificing some of the microfabricated nozzles. Figure 11 demonstrates this feature for a system of 61 nozzles, the outer ring of which consisted of 24 plugged nozzles, leaving the remaining 37 in operation. To quantify the size scatter from jet to jet, a relative standard deviation (RSD) for the average droplet size of all operating sprays is defined as

{W1365869;2} where D₁ is the average droplet diameter for jet i, and D = ∑D, In is the droplet size averaged over all jets. The uniformity of the droplet size is good, with the RSD < 0.053, which is comparable to the degree of non-uniformity in size within a single jet, as measured by an RSD of 0.09, attesting to the quasi-monodispersity requirement. Table 1 provides further details. Even small changes in droplet size from nozzle to nozzle seem to be consistent with the hierarchy of electric field intensity in Fig. 10, with a relative maximum in correspondence of the central nozzle.

Table 1 Average droplet size and Relative Standard Deviation (RSD) for the conditions of Fig. 11.

Q = QAcclh, D = 9Λ6μm

Nozzle

1 2 3 4 5 6 number 7 d (μm) 9.56 9.52 9 9.3 8.82 8.52 9.38

RSD 0.07 0.08 0.08 0.09 0.09 0.10 0.09

Q = 0.5cc/h, 5 = 10.22//;«

Nozzle 1 2 3 4 5 6 7 number d (μm) 11.15 10.47 9.85 10.21 9.91 9.5 10.47

RSD 0.08 0.08 0.09 0.10 0.10 0.08 0.09

Q = 0.6cc/h, D - = \ \Λ2μm

Nozzle 1 2 3 4 5 6 number 7

1 (μm) 12.06 11.45 10.73 l i.i : 10.74 10.3 11.49

RSD 0.08 0.09 0.09 0.10 0.11 0.09 0.09

To characterize the multiplexed system quantitatively, under the same conditions as above and with the outermost nozzles plugged, the inventors related the behavior of the multi-jet regime to the better-known single electrospray cone-jet mode. To that end, the average current per jet was compared to that measured in a separate experiment in which all protrusions but one were cut off and the corresponding holes plugged, to generate a single cone-jet regime. With the electrospray in the multiplexed regime, the total current was measured and the number of jets was counted, with the ratio of the values yielding the average current per jet, which results are plotted in Fig. 12.

{W1365869;2} It appears that the average current per jet obeys the same power law as in the single cone-jet mode, which suggests that space charge are not limiting under the present conditions and that each cone-jet behaves in the same way, regardless of the mode. 5

The performance of the multiplex system with a flow homogenizer was also examined in which F_Sj » F_Si,F_S}. To achieve a more uniform behavior and minimize the

„ . criticality in the uniformity of the electric field from nozzle to nozzle, one can revisit the momentum balance and consider the other limiting case, either with a homogenizer in the

10 reservoir that introduces a pressure drop such that F_Sι » F_Si,F_S} or using nozzles that have sufficiently small inner diameter so that F_s » F₅₃ . In both cases, the system performance is freed from the influence of edge effects in the electric field distribution and the "firing" pattern improves. As an example, the use of a flow homogenizer was demonstrated by inserting glass beads measuring 0.25 mm in average diameter and

15 sandwiching them between stainless steel filter grade woven wire cloths with 26 micron opening width. With this modification, all 91 nozzles fired simultaneously at a minimum average flow rate of 0.275cc/h, which is comparable to the minimum flow rate of an isolated cone-jet electrospray (0.2 cc/h). The spread in average size from jet to jet was found to be more pronounced than under the conditions of Fig. 10, with an RSD of 0.21,

20 even though each jet was still quasi-monodisperse with a typical RSD < 0.15. The reason for the greater nonuniformity is that the nozzle inner diameter, the glass beads and the mesh holes are all comparable in size. As a result, the packed bed fails to deliver the liquid evenly, i.e. at the same flow rate for each nozzle, but nevertheless downplays the role of electric field nonuniformities in nozzle "misfire". This undesirable behavior can be easily

25 remedied by improving the design of a relatively high-pressure drop flow homogenizer, such as by using ultrafine porous filters.

Furthermore, using microlithographic fabrication, one may multiplex by several orders of magnitudes while using the same nozzle density and identical fabrication

30 process. For example, maintaining the same packing density, but applying the mask to an entire wafer, with a diameter of approximately 10 cm, would yield the realization of

2.OxIO⁴ parallel sources in a relatively small footprint.

{W1365869;2} While the invention has been particularly shown and described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that changes in form and details may be made therein without departing from the scope and spirit of the invention.

{W1365869;2}

Claims

WHAT IS CLAIMED IS:

1. A microfabricated multiplex system for electrospraying monodisperse fluid droplets, the system comprising: a) a distribution plate formed using a fabrication technique selected from the group consisting of micro-electro mechanical fabrication, micromolding, and combinations of the foregoing, to create an integral array of substantially uniform nozzles in the distribution plate, wherein the nozzles protrude to a selected height from a surface of the distribution plate; b) at least one extractor electrode array positionable at a distance from the top of the array of protruding nozzles;

. c) at least one insulating spacer arranged between the distribution plate and at least one the extractor electrode array to position the at least one extractor electrode array at the desired distance from the top of the array of protruding nozzles; d) a source of fluid operably connected to the distribution plate for providing the fluid to be electrosprayed; and e) electrical means for maintaining a desired voltage drop between the distribution plate and the at least one extractor electrode array.

2. The multiplex system according to claim 1, wherein a micromachined master of the distribution plate is formed and the distribution plate is cast from the micromachined master or one or more intermediate molds prepared from the micromachined master.

3. The multiplex system according to claim 1, wherein the nozzles protrude to a height of at least about 50 microns.

4. The multiplex system according to claim 1, wherein the nozzles protrude to a height of less than about 50 microns.

5. The multiplex system according to claim 1, wherein the density of the nozzles formed in the distribution plate is between about 100-2000 nozzles/cm².

{W1365869;2}

6. The multiplex system according to claim 1 wherein the nozzles are arranged in a hexagonal pattern.

7... - The multiplex system according to claim 1, wherein the at least one extractor electrode array comprises a plurality of holes, and each of the plurality of holes is alignable with a corresponding nozzle in the nozzle array.

8. The multiplex system according to claim 1, wherein the plurality of holes in the at least one extractor electrode array are comparable in diameter with the outside diameter of each of the nozzles of the nozzle array.

9. The multiplex system according to claim 1, wherein the at least one extractor electrode array comprises a uniform conducting material.

10. The multiplex system according to claim 9 wherein the at least one extractor electrode array comprises stainless steel.

11. The multiplex system according to claim 1, wherein the at least one extractor electrode array comprises electrodes capable of applying different voltage to an individual nozzle or group of nozzles.

12. The multiplex system according to claim 1, wherein the extractor electrode array comprises an insulating quartz plate with corresponding holes therein and individual or grouped patterned metallic electrodes, wherein the metallic electrodes comprise gold with a thin adhesion layer of chrome or titanium thereon.

13. The multiplex system according to claim 1, wherein the at least one extractor electrode array is planar and is positioned near the top of the nozzle array.

14. The multiplex system according to claim 13, wherein the at least one extractor electrode array is positioned at a distance of about 200-500 microns from the top of nozzle array.

{W1365869;2}

15. The multiplex system according to claim 1, wherein the at least one extractor electrode array is positioned downstream of the nozzle array.

16. The multiplex system according to claim 1, wherein the at least one extractor electrode array is positioned upstream of the nozzle array.

17. The multiplex system according to claim 1, wherein the at least one spacer comprises a material selected from the group consisting of glass, ceramics, and other dielectric materials.

18. The multiplex system according to claim 1 further comprising alignment pins and corresponding alignment holes to align the nozzle array with the at least one extractor electrode array.

19. The multiplex system according to claim 1 wherein the spacing, diameter, and height of each nozzle in the nozzle array is precisely controlled.

20. The multiplex system according to claim 19, wherein the lateral accuracy of the placement of the nozzles in the nozzle array is less than about 100 nm.

21. The multiplex system according to claim 19 wherein the tolerance of the outer diameter of each nozzle of the nozzle array is less than about 1 micron.

22. The multiplex system according to claim 19 wherein the tolerance of the inner diameter of each nozzle of the nozzle array is less than about 0.5 micron.

23. The multiplex system according to claim 22 wherein the tolerance of the inner diameter of each nozzle of the nozzle array is less than about 0.3 micron.

24. The multiplex system according to claim 1 wherein substantially all of the nozzles of the nozzle array operate simultaneously at approximately the same flowrate.

{W1365869;2}

25. The multiplex system according to claim 1 wherein individual nozzles or groups of nozzles in the nozzle array can be turned on/off to adjust the spray pattern of the electrosprayed fluid.

26. The multiplex system according to claim 1 wherein the source of the fluid is a reservoir and the nozzle array is attached to the fluid reservoir with a bonding agent that is non-soluble in the electrosprayed fluid.

27. The multiplex system according to claim 1, wherein the at least one extractor electrode array, at least one insulating spacer, and distribution plate are joined together using a bonding agent.

28. The multiplex system according to claim 27, wherein the bonding agent is selected from the group consisting of epoxy, liquid copper, ceramics, polymeric materials, elastomers, acrylic resins, and combinations of the foregoing.

29. The multiplex system according to claim 1, wherein the at least one extractor electrode array, at least one insulating spacer, and distribution plate are joined together by anodic bonding.

30. The multiplex system according to claim 1, further comprising: a second distribution plate comprising a second array of nozzles integrally formed therein, wherein the second distribution plate is mounted on the first distribution plate and the second array of nozzles is alignable with the array of nozzles in the first distribution plate; and a source of a second fluid to be electrosprayed operably connected to the second distribution plate; whereby the two fluids may be simultaneously electrosprayed.

31. A method of fabricating a multiplexing system comprising the steps of: a) fabricating a distribution plate using a fabrication technique selected from the group consisting of micro-electro mechanical fabrication, micromolding, and combinations of the foregoing, to create an integral array of substantially uniform nozzles

{W1365869;2} in a surface of the distribution plate, wherein the nozzles protrude to a selected height from the surface of the distribution plate; b) positioning at least one extractor electrode array at a distance from the top of the array of protruding nozzles; c) arranging at least one insulating spacer between the distribution plate and the extractor electrode array to position the at least one extractor electrode array at the desired distance from the top of the array of protruding nozzles; d) connecting the distribution plate to a source of the fluid to be electrosprayed; and e) providing an electrical connection to maintain a desired voltage drop between the distribution plate and the at least one extractor electrode array.

32. The method according to claim 31, wherein the micro-electro mechanical fabrication technique comprises the steps of: a) providing a silicon wafer having a silicon oxide mask layer on both sides; and b. patterning the silicon wafer to produce the protruding nozzle array in the desired pattern in the silicon wafer.

33. The method according to claim 32, wherein the silicon wafer is patterned using a technique selected from the group consisting of deep reactive ion etching, wet anisotropic etching, directed etching, wet etching, ion milling, ultrasonic drilling, and combination of the foregoing.

34. The method according to claim 33, wherein the silicon wafer is patterned using deep reactive ion etching.

35. The method according to claim 31, wherein the distribution plate is fabricated by micromolding, comprising the steps of: a) preparing a micromachined master of the distribution plate using silicon; b) optionally, making one or more intermediate molds from the micromachined master; and

{W1365869;2} c) casting the distribution plate from the micromachined master, or the one or more intermediate molds prepared from the micromachined master.

36. The method according to claim 35, wherein the distribution plate is cast from a material selected from the group consisting of elastomers, acrylics, glass, green ceramics, hard ceramics, silicon carbide, and combinations of the foregoing.

37. The method according to claim 31, wherein the at least one extractor electrode array is microfabricated using photolithography and etching to provide a plurality of holes that are each alignable with a corresponding nozzle in the nozzle array of the distribution plate.

38. The method according to claim 37, wherein the plurality of holes in the at least one extractor electrode array are comparable in diameter with the outside diameter of each of the nozzles of the nozzle array.

39. The method according to claim 31, wherein the multiplex system is fabricated so that L ~ h ~ Ii_n, wherein L is the distance from the top of the nozzle protrusion in the nozzle array to the at least one extractor electrode array, h is the height of the nozzle protrusion of each of the nozzles in the nozzle array, and Ij_n is the distance between each of the nozzles of the nozzle array as measured from a centerpoint of each nozzle.

40. The method according to claim 31, wherein the average droplet size of the electrosprayed droplets exiting each nozzle has a relative standard deviation of less than about 0.1.

41. The method according to claim 31, wherein the electrosprayable fluid is selected from the group consisting of biomaterials, ceramic oxides, quantum dots, coatings, and combinations of the foregoing.

42. The method according to claim 31, wherein the nozzles protrude to a height of at least about 50 microns.

{W1365869;₂}

43. The method according to claim 31 , wherein the nozzles protrude to a height of less than about 50 microns.

44. The method according to claim 31, wherein the density of the nozzles in the distribution plate is between about 100-2000 nozzles/cm².

45. The method according to claim 31, wherein the nozzles are arranged in a hexagonal pattern.

46. The method according to claim 31, wherein the at least one extractor electrode array comprises a uniform conducting material.

47. The method according to claim 46, wherein the at least one extractor electrode array comprises stainless steel.

48. The method according to claim 31, wherein the at least one extractor electrode array comprises electrodes capable of applying different voltage to an individual nozzle or group of nozzles.

49. The method according to claim 31, wherein the extractor electrode array comprises an insulating quartz plate with corresponding holes therein and individual or grouped patterned electrodes, wherein the metallic electrodes comprise gold with a thin adhesion layer of chrome or titanium thereon.

50. The method according to claim 31, wherein the at least one extractor electrode array is positioned at a distance of 200-500 microns from the top of the nozzle protrusions of the nozzle array.

51. The method according to claim 31, wherein the at least one extractor electrode array is positioned downstream of the nozzle array.

52. The method according to claim 31, wherein the at least one extractor electrode array is positioned upstream of the nozzle array.

{W1365869;2}

53. The method according to claim 31, comprising the step of providing alignment pins and corresponding alignment holes to align the nozzle array with the at least one extractor electrode array.

54. The method according to claim 31, comprising the step of precisely controlling the spacing, diameter, and height of each nozzle in the nozzle array.

55. The method according to claim 54, wherein the lateral accuracy of the placement of the nozzles in the nozzle array is less than about 100 nm.

56. The method according to claim 54 wherein the tolerance of the outer diameter of each nozzle of the nozzle array is less than about 1 micron.

57. The method according to claim 54 wherein the tolerance of the inner diameter of each nozzle of the nozzle array is less than about 0.5 micron.

58. The method according to claim 57 wherein the tolerance of the inner diameter of each nozzle of the nozzle array is less than about 0.3 micron.

59. The method according to claim 31, wherein substantially all of the nozzles of the nozzle array operate simultaneously at approximately the same flowrate.

60. The method according to claim 31, comprising the step of turning on/off individual nozzles of the nozzle array, whereby the spray pattern of the electrosprayable fluid is adjusted.

61. The method according to claim 31, wherein the current through the system is increased at a given flowrate by multiplexing the system, thereby distributing the total flowrate through a plurality of electrosprays .

62. The method according to claim 31, further comprising the steps of: fabricating a second distribution plate comprising a second array of nozzles, wherein the second distribution plate is mounted on the first distribution plate and the second array of nozzles is alignable with the array of nozzles in the first distribution plate; and

{W1365869;2} connecting the second distribution plate to a source of a second fluid to be electrosprayed; whereby the two fluids may be simultaneously electrosprayed.

{W1365869;2}