Methods for coating surfaces

Abstract

It can provide improved efficiency and precise coating of three-dimensional substrates. [Solution] The present invention relates to an apparatus and method for coating surfaces, including the surface of a medical device, and more particularly to coating microprotrusions on a microprotrusion array. The present invention also relates to a printhead apparatus for producing particles such as a microprotrusion array, and for coating the surface of a microprotrusion array, and to the manufacture of such apparatuses, as well as to a method for using a printhead apparatus. The present invention also relates to a high-processing printing apparatus utilizing the printhead of the present invention.

Description

Technical Field

[0001] The present invention relates to an apparatus and method for coating surfaces, including the surface of a medical device, particularly for coating micro-protrusions on a micro-protrusion array. The present invention also relates to printhead devices for manufacturing products such as micro-protrusion arrays and for coating the surface of micro-protrusion arrays, their manufacture, and methods of using the printhead devices. The present invention also relates to a high-throughput printing apparatus using the printhead of the present invention.

Background Art

[0002] Any reference in this specification to a prior publication (or information derived therefrom) or to any matter known is not, and should not be taken as, an admission, approval, or any form of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.

[0003] In recent years, attempts have been made to devise new methods of delivering drugs and other bioactive substances for vaccination and other purposes, which offer alternatives that are more convenient and / or have enhanced performance compared to conventional routes of administration such as intramuscular and intradermal injection. The limitations of intradermal injection include cross-contamination due to needle stick injury among healthcare workers; injection phobia due to needles and syringes; and most importantly, the fact that needles and syringes cannot target important cells in the outer skin layer as a result of its relatively large-scale administration and the method of its administration. This represents a significant limitation to many existing and new strategies for the prevention, treatment, and monitoring of a range of untreatable diseases. There is also a need to reduce the amount of substance delivered, either due to the toxicity of the material or the need to conserve materials due to difficult or expensive manufacture.

[0004] In an effort to address some of the problems referenced above, microprojection arrays or microneedle arrays have been used to deliver various substances through the skin. For example, International Publication No. 2005 / 072630 describes a device for delivering bioactive substances and other stimuli to living cells. The device comprises a number of projections that can penetrate the skin to deliver the bioactive substance or stimuli to a predetermined site. The projections may be solid, and the donor ends of the projections are designed to be inserted into target cells or specific sites on the skin. Other devices utilizing solid or biodegradable microprojections and / or microneedles are described below.

[0005] One of the challenges of using devices containing microneedles and / or microprojections is the need to coat the projections. Various coating techniques have been described, such as immersing the array in a coating solution or spraying the coating onto the projections. For example, Gill and Prausnitz, J. Controlled Release (2007), 117: 227-237, describe coating microprojections by immersing them in a coating solution reservoir through immersion holes spaced apart according to the microprojection array. Cormier et al, J. Controlled Release (2004), 97: 503-511, describe coating a microneedle array by partial immersion in an aqueous solution containing an active compound and polysorbate. International Publication No. 2009 / 079712 describes a method for coating a microprojection array by spray coating the microprojections and drying the sprayed aqueous solution with a gas.

[0006] Inkjet printing has been used to deposit pharmaceutical compounds onto various devices and media. For example, Wu et al. (1996), J. Control. Release 40: 77-87, describes the use of inkjet for manufacturing devices containing model drugs; Radulescu et al. (2003), Proc. Winter Symposium, and 11th International The Symposium on Recent Advances in Drug Delivery Systems describes the preparation of small-diameter poly(lactic acid-glycolic acid copolymer) nanoparticles containing paclitaxel using a piezoelectric inkjet printer; Melendez et al. (2008), J. Pharm. Sci. 97: 2619-2636 utilize an inkjet printer to provide a solid-state drug delivery form of prednisolone; Desai et al. (2010), Mater. Sci. Eng. B 168: 127-131 use a piezoelectric inkjet printer to deposit an aqueous sodium alginate solution containing rhodamine R6G dye onto a calcium chloride surface; Sandler et al. (2011), J. Pharm. Sci. 100: 3386-3395 use inkjet printing to deposit various pharmaceutical compounds onto a porous paper substrate; Scoutaris et al. (2012), J. Mater. Sci.Mater.Med.23: 385-391 describes the use of inkjet printing to produce dot arrays containing two pharmacological agents and two polymers. Inkjet printing has also been used to deposit various pharmaceutical compounds onto stents (Tarcha et al. (2007) Ann.Biomed.Eng.35: 1791-1799). More recently, piezoelectric inkjet printers have been used to coat microneedles. Boehm et al. (2014) Materials Today 17(5): Sections 247-252 describe the use of an inkjet printer to coat microneedles prepared from a biodegradable acid anhydride complex containing alternating methyl vinyl ether groups and maleic anhydride groups with miconazole.

[0007] DNA microarray spotting is traditionally achieved by using a computer-controlled xyz motion stage with a head carrying a pen device to pick up droplets of aqueous solution from a multiwell plate and transfer and spot them onto the surface. These spotting pens are sophisticated designs adapted from quill-type ink pens. Pen printing is reliable and reproducible when using flat, solid surface substrates. When using non-uniform, film-type substrates, contact technique can be problematic. Non-flat substrates can result in missing spots when the surface area is lower than the level of one or more pens in the printing pen bank. Spotting onto films can result in unacceptable surface depressions and non-uniform spotting if the film absorbs the spotting solution too quickly. Other drawbacks include limited volume control for each spot printed and the inability to overprint without the risk of cross-contamination of the spotted fluid. All current jetting and printing platform designs have a movable gantry above the work surface. This is detrimental to sterile or GMP manufacturing because it generates fine particles above the work surface.

[0008] Positive pressure displacement is another spotting method that utilizes a syringe system or valve jet for fluid deposition. In valve jet technology, the opening or nozzle is mounted on a solenoid valve, which rapidly opens and closes to generate an intermittent stream of droplets from a pressurized fluid. Syringe systems pick up fluid from a sample cavity and then use positive pressure displacement to distribute the fluid onto the substrate. These systems are reliable because the influence of fluid properties on distribution is smaller than that on piezoelectric microdistribution. However, these positive pressure displacement microdistribution systems may have lower reproducibility when distributing at lower volume capacities. In these systems, the lower limit of deposition volume is in the nanoliter range.

[0009] In a drop-on-demand piezoelectric microdistributor, the fluid is maintained at ambient pressure, and a piezoelectric transducer is used to generate droplets only when needed. The transducer causes a volume change in the fluid, resulting in a pressure wave. The pressure wave travels to an opening, is converted into fluid velocity, and as a result, droplets are ejected from the opening. Alternatively, the piezoelectric transducer generates acoustic pulses that alter the fluid meniscus profile at the opening.

[0010] As a non-contact printing process, the accuracy of inkjet distribution is not affected by how the fluid wets the substrate, as in the case of pen transfer systems or positive pressure displacement where the fluid is "brought into contact" with the substrate during distribution. Therefore, the fluid source cannot be contaminated by fluid already present on the substrate or by the substrate material. Thus, it is possible to overprint multiple spots using different reagents or biological fluids without the risk of cross-contamination. Finally, the ability to freely flick fluid droplets over distances of more than a millimeter allows the fluid to be distributed to multiple depressions or other substrate features.

[0011] Current inkjet systems used to coat medical devices containing micro-protrusion arrays utilize an XYZ gantry system. The XYZ gantry system is used to position either a single nozzle or an array of individually addressable nozzles to deliver the coating onto the micro-protrusions. The printhead rasterizes across the entire target substrate, involving axial acceleration and deceleration in each line printed. Since commercially available printheads do not match the spacing of the micro-protrusion array, the printhead must be saved (i.e., positioned at a certain angle) to make the speed increase available when using multiple nozzles, and must also have variable timing for droplet ejection. With a single nozzle, the raster motion is time-consuming, a significant factor for small substrates where motion consumes up to 50% of the time required to coat the micro-protrusion array. Existing nozzle arrays require the use of variable data to achieve the desired results, which increases system complexity and therefore cost. There is a need for novel apparatuses and methods for coating substrates containing medical device substrates such as micro-protrusion arrays that are less expensive, less complex, more accurate, and more efficient. Furthermore, these devices must be sterile to prevent contamination of the products being coated. Currently, there are no systems specifically designed for distributing substances onto surfaces for the manufacture of commercially available pharmaceutical materials. [Overview of the Initiative]

[0012] The present invention relates to apparatus and methods for coating surfaces, including the surface of medical devices, and more particularly to coating microprotrusions on microprotrusion arrays. The present invention also relates to printhead apparatuses and their manufacture, and methods for using printhead apparatuses, for producing particles such as microprotrusions and for coating the surface of microprotrusion arrays. Furthermore, the present invention relates to a high-throughput apparatus for producing a large number of coated substrates, including microprotrusion arrays, using the printheads of the present invention. In a general sense, the present invention relates to apparatus and methods for depositing materials onto substrates. The apparatus and methods of the present invention can be used to print, coat, cover, or deposit materials, particularly fluid materials, onto substrates. The apparatus and methods of the present invention can be used to coat fluids onto substrates, such as coating stents or coating microprotrusions on microprotrusion arrays. The present invention relates to apparatus for printing or coating fluids, including pharmaceutical and biological substances, onto microprotrusion arrays, which can provide improved efficiency and precise coating of three-dimensional substrates. The apparatus of the present invention provides simultaneous two-dimensional deposition of pharmacologically-grade biological materials in a sterile environment. These printing apparatuses provide coating of different antigens onto different microprotrusions of a microprotrusion array. Furthermore, the apparatus of the present invention can deposit different antigens and different adjuvants or excipients onto any of the microprotrusions on the microprotrusion array. Such biological fluids include vaccines and biopharmaceuticals, which present further challenges for coating, as the active substance may only be available at low concentrations such as 1-10 mg / ml. In other words, to achieve the target therapeutic dose, this may require multiple dosings of the substance, with drying time between dosings of the substance at each feature. Since the total amount of fluid (number of droplets) supplied is relatively high, it is important to efficiently deposit the substance (material) so that the total time for coating the substrate is not excessive.

[0013] Microprojection array patches, or inkjet coatings of other vaccines and biological platforms, enable controlled dosing and precise administration and allocation of biological agents targeting individual protrusions on the platform. Typically, microprojection array platforms have a length and width of less than 20 mm and have a two-dimensional array of evenly spaced protrusions. The number of protrusions in each direction is typically less than 100, and therefore the density of protrusions on the array is 2000–10000 / cm². 2 The amount of substance required for an effective dose is typically around 500–1000 picoliters per protrusion. Currently available printer technology is not designed to print pharmaceutical-grade substances, nor can current technology print with the precision required to provide the appropriate amount of material on each protrusion. Commercially available multi-nozzle printer heads are designed for document and graphic printing, focusing on variable data addressing capabilities, high DPI in one dimension, and small droplet sizes (typically less than 30 picoliters). These characteristics do not meet the requirements needed to manufacture inkjet coatings of microprotrusion arrays. Furthermore, commercially available printer heads do not provide cooling and mixing capabilities that would allow the biological material to remain stable during the coating process.

[0014] In a first broad embodiment, the present invention provides an apparatus for coating a substrate, comprising a pump chamber, a nozzle plate, a piezoelectric actuator, and a film plate.

[0015] In a second broad embodiment, the present invention provides an apparatus for coating a substrate, comprising a pump chamber containing a fluid; a nozzle plate attached to the pump chamber, the nozzle plate having a plurality of nozzles for distributing the fluid; a membrane plate; and a piezoelectric actuator that presses the membrane plate so that the fluid is distributed through the nozzles.

[0016] Typically, the piezoelectric actuator is a piezoelectric stacked actuator.

[0017] Typically, the piezoelectric actuator is a piezoelectric unimorph actuator.

[0018] The device further includes a device for mixing the fluid.

[0019] The device further includes a housing.

[0020] The housing of the device can include a cooling device.

[0021] The pump chamber plate further includes one or more fluid ports through which the fluid is pumped into the pump chamber.

[0022] Typically, the nozzle plate has a plurality of fluid ports.

[0023] Typically, the plurality of nozzles are made of etched silicon.

[0024] Typically, the plurality of nozzles are made of electroformed nickel.

[0025] Typically, the plurality of nozzles are made of EDM stainless steel.

[0026] Typically, the plurality of nozzles are made of mechanically punched stainless steel.

[0027] Typically, the plurality of nozzles are made of laser-perforated stainless steel.

[0028] Typically, the plurality of nozzles are made in a two-dimensional array.

[0029] Typically, the diameter of the nozzles is about 30 μm to 200 μm.

[0030] Typically, the number of nozzles in the two-dimensional array is between 100 and 5000.

[0031] Typically, the number of nozzles in each dimension (each size) is the same.

[0032] Typically, the spacing between the multiple nozzles is approximately 80 to 800 micrometers.

[0033] Typically, each nozzle dispenses approximately 30 to 3000 picoliters of fluid.

[0034] Typically, the multiple nozzles are coated to increase their durability.

[0035] Typically, the multiple nozzles are coated to enhance their hydrophobicity.

[0036] Typically, the fluid is a biological substance.

[0037] Typically, the fluid is a vaccine.

[0038] Typically, the pump chamber is molded.

[0039] Typically, the apparatus is pre-primed with a priming solution.

[0040] Typically, the membrane plate is made of stainless steel.

[0041] Typically, the apparatus is sterile.

[0042] Typically, the multiple nozzles are sterile.

[0043] Typically, the device is disposable.

[0044] Typically, the nozzle plate is disposable.

[0045] Typically, the pump chamber is disposable.

[0046] Typically, the biological fluid is kept sterile.

[0047] Typically, the vaccine is kept sterile.

[0048] In a third broad embodiment, the present invention provides a method for coating a micro-protrusion array, the method comprising the steps of aligning the apparatus of claim 1 on a micro-protrusion array including a plurality of micro-protrusions such that each nozzle aligns on a micro-protrusion, and operating the actuator such that the film plate pushes fluid through the plurality of nozzles onto the plurality of micro-protrusions, thereby coating the micro-protrusion array.

[0049] In a fourth broad embodiment, the present invention provides a method for coating microprotrusions on a microprotrusion array to a predetermined volume, the method comprising the steps of: aligning the apparatus of claim 1 on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a microprotrusion; operating the actuator to cause the film plate to push fluid through the plurality of nozzles onto the plurality of microprotrusions; and repeating the previous step to coat the plurality of microprotrusions to a predetermined volume.

[0050] In a fifth broad embodiment, the present invention provides a method for coating microprotrusions on a microprotrusion array, the method comprising: aligning the apparatus of claim 1 on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a first set of uncoated microprotrusions; activating the actuator so that the membrane plate pushes fluid through the plurality of nozzles onto the first set of microprotrusions, thereby coating the microprotrusions; moving the microprotrusion array relative to the apparatus so that the plurality of nozzles align on a second set of uncoated microprotrusions; and activating the actuator so that the membrane plate pushes fluid through the plurality of nozzles onto the second set of microprotrusions, thereby coating the microprotrusions.

[0051] Typically, the multiple nozzles are located about 50 to 2000 micrometers from the multiple microprotrusions.

[0052] Typically, the alignment of the device on the array of micro-protrusions is achieved by using a camera.

[0053] In a sixth broad embodiment, the present invention provides a method for coating microprotrusions on a microprotrusion array, the method comprising: aligning an apparatus on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a first set of uncoated microprotrusions; acting an actuator so that the membrane plate extrudes a first fluid through the plurality of nozzles onto the first set of microprotrusions, thereby coating the plurality of microprotrusions; moving the microprotrusion array relative to the apparatus so that the plurality of nozzles align on a second set of uncoated microprotrusions; and acting an actuator so that the membrane plate extrudes a second fluid through the plurality of nozzles onto the second set of microprotrusions, thereby coating the plurality of microprotrusions.

[0054] In a seventh broad embodiment, the present invention provides a method for coating microprotrusions on a microprotrusion array, the method comprising the steps of: aligning the apparatus of claim 1 on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a microprotrusion; acting the actuator to push a first fluid onto the plurality of microprotrusions through the plurality of nozzles; and acting the actuator to push a second fluid onto the plurality of microprotrusions through the plurality of nozzles.

[0055] In an eighth broad embodiment, the present invention provides an apparatus for coating one or more microprotrusions on a microprotrusion array, the apparatus comprising a housing, a piezoelectric actuator, a restrictor plate, a membrane plate, a pump chamber, a lowering plate, and a nozzle plate, wherein the piezoelectric multilayer actuator is operably coupled to the membrane plate such that when the piezoelectric multilayer actuator is actuated, the piezoelectric multilayer actuator presses the membrane plate.

[0056] Typically, there is one or more ports attached to the pump chamber.

[0057] The device may further include a second restrictor plate.

[0058] In a ninth broad embodiment, the present invention provides an apparatus for coating one or more microprojections on a microprojection array, the apparatus comprising a housing connected to a pump chamber attached to a lowering plate attached to a nozzle plate, the housing and the pump chamber comprising a piezoelectric multilayer actuator operably connected to the film plate such that when the piezoelectric multilayer actuator is operated, the piezoelectric multilayer actuator presses the film plate.

[0059] Typically, there is one or more ports attached to the pump chamber.

[0060] The device may further include a second restrictor plate.

[0061] In a tenth broad embodiment, the present invention provides an apparatus for printing a material onto a substrate, the apparatus comprising: an upper plate including a single inlet hole and a single outlet hole, detachably connected to a fluid distribution plate; a fluid distribution plate including one or more reservoirs detachably connected to a piezoelectric film plate; a piezoelectric film plate including a piezoelectric device and a film beneath the piezoelectric device, the piezoelectric film plate detachably connected to a piezoelectric deformation clearance plate, the film being deformed when the piezoelectric device is activated; a piezoelectric deformation clearance plate detachably connected to a pump chamber plate; a pump chamber plate detachably connected to a nozzle plate; and a nozzle plate including a plurality of nozzles capable of discharging a fluid material onto the substrate.

[0062] Typically, the upper plate, fluid distribution plate, piezoelectric film plate, piezoelectric deformation clearance plate, pump chamber plate, and nozzle plate are all housed within the housing.

[0063] Typically, the nozzle plate has a thickness of approximately 200 to 500 μm.

[0064] Typically, the thickness of the pump chamber is less than 1 mm.

[0065] Typically, the nozzle geometric shapes of the plurality of nozzles within the nozzle plate are continuous and have no singularities.

[0066] Typically, the pump chamber plate has a plurality of ventilation holes.

[0067] Typically, the nozzle plate has a plurality of ventilation holes.

[0068] Typically, the multiple nozzle plate vents are connected to the multiple pump chamber plate vents.

[0069] Typically, the plurality of ventilation holes have a diameter of 50 μm or less.

[0070] Typically, the pump chamber plate has two restrictors.

[0071] Typically, the nozzle plate comprises two plates, including a lowering plate.

[0072] In an eleventh broad embodiment, the present invention relates to a single printhead coating apparatus comprising an X, Y translation stage on which a micro-protrusion array can be mounted, a reference camera having LED illumination (LED light), and a Z stage on which a rotating printhead is mounted.

[0073] The print head coating apparatus may further include a base to which the stage is attached.

[0074] Typically, the translation stage has a positional accuracy of ±1 μm.

[0075] Typically, the translational stage can move at speeds up to 500 mm / s.

[0076] Typically, the translation stage has a speed of 5000 mm / s 2 It has acceleration up to [a certain value].

[0077] The broad embodiments of the present invention and their respective features may be used together, interchangeably, and / or independently, and references to separate broad embodiments are not intended to be limiting. [Brief explanation of the drawing]

[0078] Various examples and embodiments of the present invention are described below with reference to the accompanying drawings. [Figure 1] This is an exploded schematic front view of one embodiment of the print head device of the present invention. [Figure 2] This is an exploded schematic partial side view of one embodiment of the print head device of the present invention. [Figure 3] This is an exploded schematic front view of one embodiment of the print head device of the present invention. [Figure 4] This is an exploded schematic partial side view of one embodiment of the print head device of the present invention. [Figure 5] This is an exploded schematic front view of one embodiment of the print head device of the present invention. [Figure 6] This is an exploded schematic partial side view of one embodiment of the print head device of the present invention. [Figure 7A] This is a diagram of one embodiment of a pump room. [Figure 7B] This is a diagram of one embodiment of a pump room. [Figure 8] This is a schematic diagram of one embodiment of a nozzle plate. [Figure 9] This is a schematic diagram of one embodiment of a piezoelectric multilayer actuator. [Figure 10A] This is a side view of one embodiment of an assembled printhead. [Figure 10B] This is a rotated side view of one embodiment of an assembled print head. [Figure 11] This is a schematic diagram of one embodiment of the print head device of the present invention. [Figure 12] This is a schematic diagram of one embodiment of a restrictor plate in a printhead device of the present invention. [Figure 13] This is a schematic isometric view of one embodiment of the print head of the present invention. [Figure 14A] This is a schematic isometric view of one embodiment of the print head of the present invention. [Figure 14B] This is a schematic bottom view of one embodiment of the print head of the present invention. [Figure 14C] This is a schematic side view of one embodiment of the print head of the present invention. [Figure 15A] This is a schematic side view of one embodiment of the print head of the present invention. [Figure 15B]This is a schematic top view of one embodiment of the print head of the present invention. [Figure 16A] This is a photograph of one embodiment of a nozzle plate. [Figure 16B] This is a high-magnification photograph of the back of one embodiment of a nozzle plate. [Figure 16C] This is a magnified front view photograph of one embodiment of a nozzle plate. [Figure 16D] This is a schematic diagram of one embodiment of the interaction between the nozzle plate and the lowering plate. [Figure 17] This shows one embodiment of the print head of the present invention. [Figure 18A] This is a top view of a pump room plate according to one embodiment of the pump room plate. [Figure 18B] This is a top view of an assembly of one embodiment of a pump chamber plate. [Figure 18C] This is a detailed view of a portion of a pump chamber with sharp edges that create pinning points for moving contact lines in order to slow down the speed of the edges of the moving contact lines. [Figure 19A] This is a top view of a plate assembly showing ventilation holes. [Figure 19B] Figure 19B is a top view of the nozzle plate showing the ventilation holes. [Figure 20A] This is a sequence diagram showing the filling of the chamber. [Figure 20B] This is a sequence diagram showing the filling of the chamber. [Figure 20C] This is a sequence diagram showing the filling of the chamber. [Figure 21] This is a diagram illustrating one embodiment of the mass inspection function. [Figure 22A] This is a schematic diagram of a nozzle geometric shape having a discontinuous internal profile with a single singularity. [Figure 22B] This is a schematic diagram of a nozzle geometric shape having a discontinuous internal profile with two singularities. [Figure 22C] Figure 13C is a schematic diagram of a nozzle geometric shape that has a continuous internal profile and no singularities. [Figure 23A]This is a schematic diagram of the geometric shape of a nozzle plate and a lowering plate having a discontinuous internal profile with a singularity. [Figure 23B] This is a schematic diagram of the geometric shape of a nozzle plate and a lowering plate having a continuous internal profile without singularities. [Figure 24A] This is a schematic diagram of the geometric shape of a nozzle plate and a lowering plate having a continuous internal profile without singularities. [Figure 24B] These are photographs of the geometric shapes of a nozzle plate and a lowering plate having a continuous internal profile without singularities. [Figure 25] One embodiment of a meniscus oscillation waveform is shown. [Figure 26] This is a diagram of one embodiment of an amplifier-based PZT driver. [Figure 27] This is a diagram of one embodiment of an amplifier-based PZT driver. [Figure 28] This is a diagram illustrating one embodiment of a PZT signal feedback design. [Figure 29] This is a diagram of one embodiment of a single-printhead high-speed coating apparatus. [Figure 30A] Embodiments are shown of an out-of-plane planar insertion dovetail connector for mat aggregation, i.e., an aggregation design featuring a dovetail. [Figure 30B] Embodiments are shown of an out-of-plane planar insertion dovetail connector for mat aggregation, i.e., an aggregation design featuring a dovetail. [Figure 30C] Embodiments are shown of an out-of-plane planar insertion dovetail connector for mat aggregation, i.e., an aggregation design featuring a dovetail. [Figure 31A] An embodiment is shown having an aggregation design featuring a cross-shaped end spigot for stacking out-of-plane insert connectors for mat aggregation. [Figure 31B] An embodiment is shown having an aggregation design featuring a cross-shaped end spigot for stacking out-of-plane insert connectors for mat aggregation. [Figure 32A]The present invention illustrates an embodiment having a cohesive design featuring cruciate end spigots for stacking in-plane friction mating connectors for mat cohesiveness. [Figure 32B] The present invention illustrates an embodiment having a cohesive design featuring cruciate end spigots for stacking in-plane friction mating connectors for mat cohesiveness. [Figure 33A] This embodiment demonstrates how strong matting cohesiveness in a compact stack is achieved with hexagonal and multiple spigots. [Figure 33B] This embodiment demonstrates how strong matting cohesiveness in a compact stack is achieved with hexagonal and multiple spigots. [Figure 34A] This embodiment shows a design that does not have a guide shaft (spigot) and instead uses an in-plane friction mating connector. [Figure 34B] This embodiment shows a design that does not have a guide shaft (spigot) and instead uses an in-plane friction mating connector. [Figure 34C] This embodiment shows a design that does not have a guide shaft (spigot) and instead uses an in-plane friction mating connector. [Figure 35A] This shows various orientations of patch embodiments that butt against each other to form a mat. [Figure 35B] This shows various orientations of patch embodiments that butt against each other to form a mat. [Figure 35C] This shows various orientations of patch embodiments that butt against each other to form a mat. [Figure 36] An embodiment of a patch mat having 100 patches is shown. [Figure 37A] This shows a single column representation of two stacked patches. [Figure 37B] This shows a cross-sectional view of 10 rows of five stacked patches within the mat. [Figure 38] This is a schematic diagram of one embodiment of a printhead having an integrated fluid reservoir contained within a cover. [Figure 39]This is a schematic diagram of one embodiment of a printhead having an integrated fluid reservoir. [Figure 40A] This is a front view of a bio-processing bag fluid reservoir, which is one embodiment of an integrated fluid reservoir. [Figure 40B] This is a side view of a bio-processing bag fluid reservoir, which is one embodiment of an integrated fluid reservoir. [Figure 41] This is a schematic diagram of the lower part of an embodiment of an integrated fluid reservoir for a print head. [Figure 42] This is a schematic diagram of one embodiment of printer connection. [Figure 43] This is a schematic diagram of one embodiment of an external fluid reservoir in which the supply line extends from the print head to the external reservoir. [Figure 44] This is a schematic diagram of one embodiment of an external fluid reservoir in which the supply line extends from the print head to an external reservoir that provides an agitation mechanism. [Figure 45] This is a schematic diagram of one embodiment of a system for controlling the operation of a print head. [Modes for carrying out the invention]

[0079] Microarray projection, or microarray patch (MAP), or micro-projection array patch, encompasses a number of different devices currently under development. Other technical terms for these devices include microneedle arrays, microprojection patches, and microneedle patches. These patches can serve as an alternative to the administration of vaccines and other pharmacological substances via cutaneous or intramuscular injection, by providing a method for administering substances through the outer layer of the skin. To patch projections formed from the vaccine or pharmacological solution itself, patches take various forms, from metal-formed patches to polymer-formed patches. The manufacture of these patches depends on the ability to deposit a dry drug solution or vaccine onto the tips of the micro-projections with high throughput and precision. Precise coating of the projections is crucial because consistent delivery of the coated substance to the patient is necessary. Too little substance delivered impairs the effectiveness of the treatment. Too much substance can lead to an overdose or at least waste expensive vaccines or drugs. The ability to rapidly coat the patches is necessary for manufacturing commercially viable products. Patch manufacturing, regardless of the method involved, must be carried out in accordance with pharmaceutical guidelines (e.g., PIC's GMP code). To satisfy both manufacturers and regulatory authorities, complete process control is required, ensuring that product quality is always well understood and controlled, and that output products are 100% monitored for non-conforming products and performance trends. Large-scale, high-speed, and high-precision deposition under the conditions required for sterile manufacturing has been difficult to verify with conventional coating processes. Methods for verifying process output at high coating speeds have not yet been addressed by the industry. As an example, regulatory authorities may anticipate encountering process analysis techniques (PATs) with the following important quality attributes: 1) the mass / volume of the distributed material is measured; 2) coating uniformity is maintained across the entire substrate; 3) the location of the coating on protrusions is verified; 4) non-conforming products are identified and removed; and 5) printhead performance (droplet size, droplet position, array uniformity) is monitored.

[0080] Commercially available inkjet printing systems are not manufactured from biocompatible materials, do not comply with GMP guidelines, and do not require the same level of process control and performance validation as required for printing pharmaceutical or biological materials. The apparatus and method of the present invention relates to an integrated control system using a novel printhead and nozzle plate design and manufacture, novel process control, a novel PZT drive waveform, and process steps of the present invention that ensure that process control and quality output are always maintained. The method and apparatus of the present invention include the design of a coating system permissible for the manufacture of combination medical devices labeled as sterile and provides a control system that complies with standards provided by global regulatory bodies.

[0081] The present invention relates to an apparatus and method for depositing a material (substance) onto a substrate. The present invention relates to an apparatus and method for depositing a material for manufacturing a device or for coating a device. The present invention relates to an apparatus and method for coating a medical device including a micro-protrusion array. The present invention relates to a novel printhead design that utilizes a piezoelectric stacked actuator as a drive component to press a membrane plate and distribute a fluid in a pump chamber through a two-dimensional nozzle array. The distributed fluid is coated onto micro-protrusions on the micro-protrusion array by aligning the nozzles with the micro-protrusions on the array. The number of nozzles in each of the two dimensions may be less than 100, and furthermore, the number of nozzles may be evenly divided by the number of protrusions in the micro-needle array to be coated, or may be the same as the number of protrusions to be coated. The spacing between nozzles may be an integer multiple of the spacing between micro-protrusions in the micro-protrusion array. The apparatus and method of the present invention are provided to enable all nozzles to simultaneously dispense a single droplet or a series of droplets having a total volume in the range of 30 to 3000 picoliters per nozzle in each droplet dispensing cycle. The apparatus and method of the present invention are provided such that each droplet dispensing cycle allows a single nozzle or a subset of nozzles to dispense a single droplet or a series of droplets.

[0082] The present invention provides an apparatus and method for a print head. In the print head, the nozzle plate provides a two-dimensional array of nozzles for distributing material.

[0083] [Print head device] One embodiment of the printhead device of the present invention is shown in Figures 1 and 2. In this embodiment of the printhead device, a piezoelectric stacked actuator is used. In Figure 1, the housing (101) is connected to a pumping chamber (106) in which the fluid to be distributed is stored. The fluid flows into the pumping chamber through one or more ports (107). The piezoelectric stacked actuator (102) is activated and strikes a plate membrane (104) held between two restrictor plates (103 and 105). When the piezoelectric stacked actuator (102) is activated, the fluid is pushed out by the plate membrane (104), passes through the lowering plate (108), exits through the nozzles in the nozzle plate (109), and is distributed onto micro-protrusions, so that the lowering plate (108) is attached to the nozzle plate (109). In this embodiment, the printhead is assembled by threading a housing (101), a first restrictor plate (103), a membrane plate (104), a second restrictor plate (105), and a pump chamber (106). The pre-loaded force on the laminated PZT (102) on the membrane plate (104) is set using a DC force gauge. The pre-loaded force is used to fine-tune the performance of different printhead assemblies so that optimal performance can be achieved. In this embodiment of the printhead, the components above the membrane plate (i.e., the housing (101), the laminated PZT (102), and the first restrictor plate (103)) can be sterilized and reused, with no fluid contact to these components. The components below the membrane plate and the membrane plate components may be disposable. The restrictor plate can act as an internal fluid conduit through which biological fluids flow to the region below the membrane plate.

[0084] Figures 3-6 provide alternative embodiments of the printhead apparatus of the present invention in which a unimorph piezoelectric unit is used. In Figure 3, the housing (301) is connected to a pump chamber (305) in which the fluid to be distributed is stored. The fluid flows into the pump chamber through one or more ports (306). The unimorph piezoelectric device (302) is activated and strikes a plate membrane (303) held by a restrictor plate (304). Once the unimorph piezoelectric device (302) is activated, the fluid is pushed out by the plate membrane (303), passes through the descending plate (307), exits through the nozzles in the nozzle plate (308), and is distributed onto micro-protrusions, as the descending plate (307) is attached to the nozzle plate (308).

[0085] Figure 5 shows an embodiment in which the housing (501) has a port (501) for directing fluid into a pump chamber (506). The Unimorph PZT (503) strikes a plate membrane (504) held in place by a restrictor plate (505). All of these components are assembled together with the housing (506), the descent plate (507), and the nozzle plate (508). Embodiments utilizing the Unimorph PZT are assembled using biocompatible epoxy. The Unimorph PZT is considerably less expensive than the multilayer PZT, and therefore can provide a completely disposable printhead with reduced manufacturing costs. Because the Unimorph PZT has less variation in performance, product performance variation can be tighter. Because the Unimorph PZT is smaller, the printhead footprint can also be smaller (e.g., 30 × 30 × 30 mm). Finally, the compliance of the Unimorph PZT is higher than that of the Multilayer PZT, and as a result, the jet performance can be better tuned than that of the Multilayer PZT version. Figure 9 shows a schematic diagram of one embodiment of a piezoelectric multilayer actuator.

[0086] Figures 10A and 10B illustrate one embodiment of an assembled printhead device. Figure 11 provides an additional embodiment of the printhead of the present invention. Components of this embodiment of the printhead include a piezoelectric device (1103), a film plate (1104), a deformation clearance plate (1101), a restrictor pump chamber (1102), and a nozzle plate (1108). The deformation clearance plate is located between the film plate and the pump chamber plate. The film plate is deformed toward the deformation clearance plate by a piezoelectric actuator, and the maximum deformable area within the film plate is determined by the deformation clearance plate. In this example, the deformation clearance plate (1101) functions similarly to the restrictor plate (105) in the above example. The restrictor pump chamber (1102), on the other hand, provides a function broadly equivalent to the pump chamber (106) in the above example. Therefore, references to specific technical terms should be understood as merely descriptive of the functions provided, and not necessarily intended to be limiting. Figure 12 provides a schematic top view of one embodiment of a restrictor pump chamber.

[0087] Figure 13 provides a schematic diagram of the printhead assembly shown in Figure 11, within a housing that includes a cartridge cap (1310), a cartridge body (1311), and an adapter plate (1312). The adapter plate may be removable to allow for replacement of the nozzle array. Figures 14A-C and 15A and B show various diagrams of the printhead assembly within the housing.

[0088] Various parts of a printhead can be assembled in a variety of ways, including but not limited to diffusion bonding, epoxy bonding, laser welding, or a combination thereof. In diffusion welding, multiple parts of the printhead assembly are coated with a bonding layer (e.g., gold), aligned, and then diffusion-bonded. Diffusion bonding may be preferred because it is a more permanent approach with less tendency for leakage and hole blockage due to adhesive seeping into holes. In epoxy bonding, a thin layer of adhesive (approximately 3 μm) is applied to each surface, the parts are aligned in a jig, and then bonded under pressure and heat. In laser welding, areas requiring watertight bonding are laser-welded for final assembly. For example, with respect to Figure 11, a piezoelectric device (1103) may be adhesively bonded to a membrane plate (1104) to form one subassembly. A deformation clearance plate (1101), a restrictor pump chamber (1102), and a nozzle plate (1108) may be diffusion-bonded to each other to form a second subassembly. These two subassemblies can then be bonded together to form a print head. Alternatively, the deformation clearance plate (1101), restrictor pump chamber (1102), and nozzle plate (1108) can be laser-welded together, and this subassembly can be bonded to a subassembly consisting of the piezoelectric device (1103) and membrane plate (1104). Another option is to bond all the parts together.

[0089] In one embodiment of the printhead of the present invention, the printhead functions as follows: The printhead has a fluid source from a reservoir, which may be integrated into the design or located externally. Initially, the fluid from the reservoir to the nozzle is stationary, i.e., there is no flow. Between the reservoir and the nozzle are a microfluidic conduit and a pump chamber. The microfluidic conduit serves to replenish the fluid from the reservoir to the pump chamber. The pump chamber serves to discharge the fluid from the nozzle. At the nozzle outlet is a meniscus or liquid / gas interface, determined by the shape of the nozzle outlet, which in some embodiments forms a rounded meniscus. In a static state, the meniscus has a concave shape. This concave shape provides a means to generate capillary pressure and maintain the fluid in the pump chamber from leaking out of the nozzle. At a certain time t=0, the piezoelectric actuator is pressurized by an electric drive signal. At t=t1, the operation of the piezoelectric actuator is completed. The actuated piezoelectric actuator then pushes a membrane plate, generating a positive pressure wave in the pump chamber. The fluid in the pump chamber propagates pressure waves in all directions, namely through the nozzle to the nozzle meniscus and through the fluid conduit to the reservoir. The pressure waves propagating to the reservoir are attenuated because the reservoir has a large free surface (a large liquid / gas interface with a lot of compliance). The pressure wave propagates to the nozzle outlet at t=t2, and if the wave pressure exceeds the capillary pressure, the fluid deforms the nozzle meniscus, changing it from a concave to a convex shape. If the pressure wave is much greater than the capillary pressure of the nozzle meniscus, the wave continues to push the fluid through the nozzle, pushing the convex meniscus into the liquid ligament. The liquid ligament breaks at the nozzle outlet at t=t3, mainly due to Rayleigh instability induced by the pressure wave itself. This action forms one or more droplets toward the substrate, typically at speeds exceeding 1 m / s. After the ligament breaks at the nozzle outlet, the residual fluid oscillates back, forming a concave nozzle meniscus. In the droplet formation process described above, due to the law of conservation of mass, the fluid in the reservoir must replenish the fluid conduit, pump chamber, and nozzle opening in an amount equal to the droplet volume.The replenishment process involves a creep flow phenomenon, where the fluid slowly creeps into the space between the reservoir and the nozzle meniscus. This phenomenon is completed at t=t4. Although residual pressure waves are still oscillating within the pump chamber, no additional droplets occur because the amplitude is smaller than the capillary pressure. At t=t5, the residual pressure waves finally attenuate and disappear. The entire system returns to a static state, ready for the next electrical signal to activate the piezoelectric actuator. The above describes one printhead droplet formation cycle. The reverse of this cycle defines the ejection frequency. Typically, t1 is less than a few microseconds, t2-t1 is less than a few microseconds, t3-t2 is less than tens of microseconds, t4 is approximately the same as t3, and t5 can be about several hundred seconds.

[0090] In embodiments of a printhead having a drop plate and a nozzle plate, the alignment of the drop plate and the nozzle plate is a critical factor in the performance of the printhead. An alignment tool can be used to align these two plates so that the holes in each drop plate and nozzle plate are aligned with each other.

[0091] In some alternative embodiments, the printhead may be configured without the deformation clearance plate or its functional equivalent as described above. While the deformation clearance plate may be used to hold in place portions of the membrane that are not used when pushing the fluid, it will be understood that similar results may be achieved using other techniques that do not necessarily require a separate deformation clearance plate, for example, by a thickened membrane or pump chamber plate. In some examples, the functions described for the deformation clearance plate may be provided by alternative structural arrangements that inevitably involve the use of a plate.

[0092] Therefore, another form of printhead device can be broadly defined as including a restrictor pump chamber containing a fluid, a nozzle configuration including a plurality of nozzles communicating with the fluid in the restrictor pump chamber, a piezoelectric actuator, and a membrane provided adjacent to the piezoelectric actuator and separated from the restrictor pump chamber, wherein the operation of the piezoelectric actuator causes the membrane to come into contact with the fluid in the restrictor pump chamber, thereby pushing the fluid into the nozzles, thereby spraying the coating liquid onto the substrate.

[0093] [nozzle] The number of nozzles in each of the two dimensions may be less than 100 nozzles, or less than 90 nozzles, or less than 80 nozzles, or less than 70 nozzles, or less than 60 nozzles, or less than 50 nozzles, or less than 40 nozzles, or less than 30 nozzles, or less than 20 nozzles, or less than 10 nozzles. The number of nozzles in a given direction is 10 to 100 nozzles, or 10 to 90 nozzles, or 10 to 80 nozzles, or 10 to 70 nozzles, or 10 to 60 nozzles, or 10 to 50 nozzles, or 10 to 40 nozzles, or 10 to 30 nozzles, or 10 to 20 nozzles, or 20 to 100 nozzles, or 20 to 90 nozzles, or 20 to 80 nozzles, or 20 to 70 nozzles, or 20 to 60 nozzles, or 20 to 50 nozzles, or 20 to 40 nozzles, or 20 to 30 nozzles, or 3 It may also be 0 to 100 nozzles, or 30 to 90 nozzles, or 30 to 80 nozzles, or 30 to 70 nozzles, or 30 to 60 nozzles, or 30 to 50 nozzles, or 30 to 40 nozzles, or 40 to 100 nozzles, or 40 to 90 nozzles, or 40 to 80 nozzles, or 40 to 70 nozzles, or 40 to 60 nozzles, or 40 to 50 nozzles, or 50 to 100 nozzles, or 50 to 90 nozzles, or 50 to 80 nozzles, or 50 to 70 nozzles, or 50 to 60 nozzles.

[0094] The nozzles may be spaced at the following intervals: approximately 50-500 micrometers, or approximately 50-450 micrometers, or approximately 50-400 micrometers, or approximately 50-350 micrometers, or approximately 50-300 micrometers, or approximately 50-250 micrometers, or approximately 50-200 micrometers, or approximately 50-150 micrometers, or approximately 50-100 micrometers, or approximately 100-500 micrometers, or approximately 100-450 micrometers. 400 micrometers, or approximately 100-400 micrometers, or approximately 100-350 micrometers, or approximately 100-300 micrometers, or approximately 100-250 micrometers, or approximately 100-200 micrometers, or approximately 100-150 micrometers, or approximately 150-500 micrometers, or approximately 150-450 micrometers, or approximately 150-400 micrometers, or approximately 150-350 micrometers, or approximately 150-300 micrometers Tor, or approximately 150-250 micrometers, or approximately 150-200 micrometers, or approximately 200-500 micrometers, or approximately 200-450 micrometers, or approximately 200-400 micrometers, or approximately 200-350 micrometers, or approximately 200-300 micrometers, or approximately 200-250 micrometers, or approximately 250-500 micrometers, or approximately 250-450 micrometers, or approximately 250-400 micrometers , or approximately 250-350 micrometers, or approximately 250-300 micrometers, or approximately 300-500 micrometers, or approximately 300-450 micrometers, or approximately 300-400 micrometers, or approximately 300-350 micrometers, or approximately 350-500 micrometers, or approximately 350-450 micrometers, or approximately 350-400 micrometers, or approximately 400-500 micrometers, or approximately 450-500 micrometers.

[0095] The density of nozzles in the nozzle array is 1 cm 2The number of nozzles per unit may be less than or equal to: approximately 1000-10000 nozzles, or approximately 1000-9000 nozzles, or approximately 1000-8500 nozzles, or approximately 1000-8000 nozzles, or approximately 1000-7500 nozzles, or approximately 1000-7000 nozzles, or approximately 1000-6500 nozzles, or approximately 1000-6000 nozzles, or approximately 1000-5500 nozzles, or approximately 1000-5000 nozzles, or approximately 1000-4500 nozzles, or approximately 1000-4000 nozzles, or approximately 1000-3500 nozzles, or approximately 1000-30 00 nozzles, or approximately 1000-2500 nozzles, or approximately 1000-2000 nozzles, or approximately 1000-1500 nozzles, or approximately 1500-10000 nozzles, or approximately 1500-9000 nozzles, or approximately 1500-8500 nozzles, or approximately 1500-8000 nozzles, or approximately 1500-7500 nozzles, or approximately 1500-7000 nozzles, or approximately 1500-6500 nozzles, or approximately 1500-6000 nozzles, or approximately 1500-5500 nozzles, or approximately 1500-5000 nozzles, or approximately 1500-4500 nozzles, and Approximately 1500-4000 nozzles, or approximately 1500-3500 nozzles, or approximately 1500-3000 nozzles, or approximately 1500-2500 nozzles, or approximately 1500-2000 nozzles, or approximately 2000-10000 nozzles, or approximately 2000-9000 nozzles, or approximately 2000-8500 nozzles, or approximately 2000-8000 nozzles, or approximately 2000-7500 nozzles, or approximately 2000-7000 nozzles, or approximately 2000-6500 nozzles, or approximately 2000-6000 nozzles, or approximately 2000-5500 nozzles, or approximately 2000- 5000 nozzles, or approximately 2000-4500 nozzles, or approximately 2000-4000 nozzles, or approximately 2000-3500 nozzles, or approximately 2000-3000 nozzles, or approximately 2000-2500 nozzles, or approximately 2500-10000 nozzles, or approximately 2500-9000 nozzles, or approximately 2500-8500 nozzles, or approximately 2500-8000 nozzles, or approximately 2500-7500 nozzles, or approximately 2500-7000 nozzles, or approximately 2500-6500 nozzles, or approximately 2500-6000 nozzles, or approximately 2500-5500 nozzles,Or approximately 2500-5000 nozzles, or approximately 2500-4500 nozzles, or approximately 2500-4000 nozzles, or approximately 2500-3500 nozzles, or approximately 2500-3000 nozzles, or approximately 3000-10000 nozzles, or approximately 3000-9000 nozzles, or approximately 3000-8500 nozzles, or approximately 3000-8000 nozzles, or approximately 3000-7500 nozzles, or approximately 3000-7000 nozzles, or approximately 3000-6500 nozzles, or approximately 3000-6000 nozzles, or approximately 3000-5500 nozzles, or approximately 3000 ~5000 nozzles, or approximately 3000~4500 nozzles, or approximately 3000~4000 nozzles, or approximately 3000~3500 nozzles, or approximately 3500~10000 nozzles, or approximately 3500~9000 nozzles, or approximately 3500~8500 nozzles, or approximately 3500~8000 nozzles, or approximately 3500~7500 nozzles, or approximately 3500~7000 nozzles, or approximately 3500~6500 nozzles, or approximately 3500~6000 nozzles, or approximately 3500~5500 nozzles, or approximately 3500~5000 nozzles, or approximately 3500~4500 nozzles, Or approximately 3500-4000 nozzles, or approximately 4000-10000 nozzles, or approximately 4000-9000 nozzles, or approximately 4000-8500 nozzles, or approximately 4000-8000 nozzles, or approximately 4000-7500 nozzles, or approximately 4000-7000 nozzles, or approximately 4000-6500 nozzles, or approximately 4000-6000 nozzles, or approximately 4000-5500 nozzles, or approximately 4000-5000 nozzles, or approximately 4000-4500 nozzles, or approximately 4500-10000 nozzles, or approximately 4500-9000 nozzles, or approximately 4500 ~8500 nozzles, or approximately 4500~8000 nozzles, or approximately 4500~7500 nozzles, or approximately 4500~7000 nozzles, or approximately 4500~6500 nozzles, or approximately 4500~6000 nozzles, or approximately 4500~5500 nozzles, or approximately 4500~5000 nozzles, or approximately 5000~10000 nozzles, or approximately 5000~9000 nozzles, or approximately 5000~8500 nozzles, or approximately 5000~8000 nozzles, or approximately 5000~7500 nozzles, or approximately 5000~7000 nozzles, or approximately 5000~6500 nozzles,Or approximately 5000-6000 nozzles, or approximately 5000-5500 nozzles, or approximately 5500-10000 nozzles, or approximately 5500-9000 nozzles, or approximately 5500-8500 nozzles, or approximately 5500-8000 nozzles, or approximately 5500-7500 nozzles, or approximately 5500-7000 nozzles, or approximately 5500-6500 nozzles, or approximately 5500-6000 nozzles.

[0096] In the simplest scenario, the number of nozzles directly corresponds to the number of protrusions on the microprotrusion array. For example, if a two-dimensional nozzle array has 38 × 38 nozzles (1444 nozzles in total), the microprotrusion array has 1444 protrusions in the same spatial arrangement as the nozzle array for a one-to-one correspondence. In this case, the spacing between the microprotrusions on the microprotrusion array is the same as the spacing between the nozzles. In some cases, the spacing between the microprotrusions may be closer than the spacing between the nozzles. For example, if the spacing between microprotrusions on the microprotrusion array is 120 micrometers, the spacing between nozzles may be 240 micrometers so that each nozzle covers every other microprotrusion. In this case, the correspondence between nozzles and microprotrusions is 1:2. For example, if the spacing between microprotrusions on the microprotrusion array is 120 micrometers, the spacing between nozzles may be 480 micrometers so that each nozzle coats every three microprotrusions. In this case, the correspondence between nozzles and microprotrusions is 1:4.

[0097] By making the nozzle pitch equal to the projection pitch and generating the same 2D array across multiple nozzles to match the projection array, the design is not limited to uniform square or rectangular arrays, but can print abstract geometric shapes (smiles, circles, etc.). Furthermore, there is no need to move the print head across the array, and the above array speeds up the process and improves target setting accuracy.

[0098] In some embodiments of the apparatus and method of the present invention, the nozzle array of the printhead does not coat all the microprotrusions designed for coating in a single pass. For example, if the nozzle array is a two-dimensional array with 38 × 38 nozzles, and the microprotrusion array has 5776 microprotrusions arranged as a 76 × 76 array, the nozzles may need to move relative to the microprotrusion array. In such a scenario, the microprotrusion array can be seen as having four quadrants, each with 1444 microprotrusions. To coat the protrusions of the entire array, the printhead carrying the nozzles may move relative to the microprotrusion array three times after the initial positioning so that each quadrant can be coated. Alternatively, the microprotrusion array may be moved relative to the printhead, and then the four quadrants may be coated again. Similarly, any microprotrusion array having an integer multiple of the number of nozzles can be coated by the printhead by moving the printhead or the microprotrusion array relative to each other so that the nozzles align on the microprotrusions in each quadrant. Also, as described above, multiple microprotrusions in the microprotrusion array can be positioned closer to each other than the nozzles of the printhead. For example, the microprotrusion array may have 11,552 microprotrusions, and the nozzle array has 38 × 38 nozzles aligned for every other microprotrusion. The microprotrusion array and the nozzle array can be moved relative to each other so that the nozzle array coats every other microprotrusion in the first or fourth quadrant, then coats the second quadrant of the microprotrusion array, and similarly so that the entire microprotrusion array having every other coated microprotrusion is coated.

[0099] Nozzles can be arranged on a nozzle plate as shown in Figures 16A-D. A two-dimensional array of nozzles can be manufactured from materials such as etched silicon or electroformed nickel, but is not limited to these. The nozzle plate can be mounted on a descending plate (Figure 16D), which is mounted on a pump chamber (Figure 7), and the combination of the nozzle plate / descending plate and the pump chamber is sealed, allowing the inflow of fluid to be distributed through the nozzles in the nozzle plate. When silicon or stainless steel plates are used, the descending plate and nozzle plate can be mounted by direct bonding, then either epoxy bonding or diffusion bonding may be used. Alternatively, there may be a single nozzle plate without a descending plate. If there is only one plate below the pump chamber plate, it is called a nozzle plate. However, if two plates are used to make a nozzle plate, the upper plate is called a descending plate and the lower plate is called a nozzle plate.

[0100] In one embodiment, the nozzle plate and the lowering plate are 20 × 20 mm squares. In one embodiment, the thickness of the nozzle plate is 0.05 to 0.1 mm, and the thickness of the lowering plate is 0.10 to 0.25 to 1.0 mm. The nozzle plate may be coated to enhance durability and hydrophobicity. The nozzle plate may also have fluid ports molded or machined into the plate, which allow the pump chamber to be filled and the fluid recirculated during the coating process. (Figure 8) Recirculation of the fluid during the coating process can provide fluid mixing.

[0101] The droplet size can be determined by the energy of the droplet mass. If the droplet is too large, it will not remain on the top of the protrusion but will slide down the protrusion toward the substrate. If the droplet is too large, it may extend over two or more protrusions. If the droplet is too small, the above process becomes inefficient. Stability data indicates that smaller droplets that dry faster may offer a longer shelf life (expiration date). The droplet size can be less than 500 pl, or less than 400 pl, or less than 300 pl, or less than 200 pl, or less than 100 pl. The droplet size may be in the range of approximately 10pl to 500pl, 10pl to 400pl, 10pl to 300pl, 10pl to 300pl, 10pl to 200pl, 10pl to 100pl, 10pl to 50pl, 50pl to 500pl, 50pl to 400pl, 50pl to 300pl, 50pl to 200pl, 50pl to 100pl, 100pl to 500pl, 100pl to 400pl, 100pl to 300pl, 100pl to 200pl, 200pl to 500pl, 200pl to 400pl, and 200pl to 300pl. The droplet size may be approximately 100 pl, or 105 pl, or 110 pl, or 115 pl, or 120 pl, or 125 pl, or 130 pl, or 135 pl, or 140 pl, or 145 pl, or 150 pl.

[0102] Each droplet dispensing cycle allows all nozzles to simultaneously dispense a single droplet or a series of droplets, with a total volume within the following ranges: 20–3000 picoliters, or 20–2500 picoliters, or 20–2000 picoliters, or 20–1500 picoliters, or 20–1000 picoliters, or 20–900 picoliters, or 20–800 picoliters, or 20–700 picoliters, or 20–600 picoliters, or 20–500 picoliters, or 20–400 picoliters, or 20–300 picoliters, or 20–200 picoliters, or 20–100 picolites. Lu, or 20-90 picoliters, or 20-80 picoliters, or 20-70 picoliters, or 20-60 picoliters, or 20-50 picoliters, or 20-40 picoliters, or 20-30 picoliters, or 30-3000 picoliters, or 30-2500 picoliters, or 30-2000 picoliters, or 30-1500 picoliters, or 30-1000 picoliters, or 30-900 picoliters, or 30-800 picoliters, or 30-700 picoliters, or 30-600 picoliters, or 30-500 picoliters, or 30-400 picoliters, or 30-300 picoliters, or 30-200 picoliters, or 30-100 picoliters, or 30-90 picoliters, or 30-80 picoliters, or 30-70 picoliters, or 30-60 picoliters, or 30-50 picoliters, or 30-40 picoliters, or 40-3000 picoliters, or 40-2500 picoliters, or 40- 2000 picoliters, or 40-1500 picoliters, or 40-1000 picoliters, or 40-900 picoliters, or 40-800 picoliters, or 40-700 picoliters, or 40-600 picoliters, or 40-500 picoliters, or 40-400 picoliters, or 40-300 picoliters, or 40-200 picoliters, or 40-100 picoliters, or 40-90 picoliters, or 40-80 picoliters, or 40-70 picoliters,Or 40-60 picoliters, or 40-50 picoliters, or 50-3000 picoliters, or 50-2500 picoliters, or 50-2000 picoliters, or 50-1500 picoliters, or 50-1000 picoliters, or 50-900 picoliters, or 50-800 picoliters, or 50-700 picoliters, or 50-600 picoliters, or 50-500 picoliters, or 50-400 picoliters, or 50-300 picoliters, or 50-200 picoliters, or 50-1 00 picoliters, or 50-90 picoliters, or 50-80 picoliters, or 50-70 picoliters, or 50-60 picoliters, or 60-3000 picoliters, or 60-2500 picoliters, or 60-2000 picoliters, or 60-1500 picoliters, or 60-1000 picoliters, or 60-900 picoliters, or 60-800 picoliters, or 60-700 picoliters, or 60-600 picoliters, or 60-500 picoliters, or 60-400 picoliters, Or 60-300 picoliters, or 60-200 picoliters, or 60-100 picoliters, or 60-90 picoliters, or 60-80 picoliters, or 60-70 picoliters, or 70-3000 picoliters, or 70-2500 picoliters, or 70-2000 picoliters, or 70-1500 picoliters, or 70-1000 picoliters, or 70-900 picoliters, or 70-800 picoliters, or 70-700 picoliters, or 70-600 picoliters, or 70-50 0 picoliters, or 70-400 picoliters, or 70-300 picoliters, or 70-200 picoliters, or 70-100 picoliters, or 70-90 picoliters, or 70-80 picoliters, or 80-3000 picoliters, or 80-2500 picoliters, or 80-2000 picoliters, or 80-1500 picoliters, or 80-1000 picoliters, or 80-900 picoliters, or 80-800 picoliters, or 80-700 picoliters, or 80-600 picoliters,Or 80-500 picoliters, or 80-400 picoliters, or 80-300 picoliters, or 80-200 picoliters, or 80-100 picoliters, or 80-90 picoliters, or 90-3000 picoliters, or 90-2500 picoliters, or 90-2000 picoliters, or 90-1500 picoliters, or 90-1000 picoliters, or 90-900 picoliters, or 90-800 picoliters, or 90-700 picoliters, or 90-600 picoliters, or 9 0-500 picoliters, or 90-400 picoliters, or 90-300 picoliters, or 90-200 picoliters, or 90-100 picoliters, or 100-1000 picoliters, or 100-900 picoliters, or 100-800 picoliters, or 100-700 picoliters, or 100-600 picoliters, or 100-500 picoliters, or 100-400 picoliters, or 100-300 picoliters, or 100-200 picoliters, or 200-1000 picoliters, Or 200-900 picoliters, or 200-800 picoliters, or 200-700 picoliters, or 200-600 picoliters, or 200-500 picoliters, or 200-400 picoliters, or 200-300 picoliters, or 300-1000 picoliters, or 300-900 picoliters, or 300-800 picoliters, or 300-700 picoliters, or 300-600 picoliters, or 300-500 picoliters, or 300-400 picoliters, or 400-10 00 picoliters, or 400-900 picoliters, or 400-800 picoliters, or 400-700 picoliters, or 400-600 picoliters, or 400-500 picoliters, or 500-1000 picoliters, or 500-900 picoliters, or 500-800 picoliters, or 500-700 picoliters, or 500-600 picoliters, or 600-1000 picoliters, or 600-900 picoliters, or 600-800 picoliters, or 600-700 picoliters,Or 700-1000 picoliters, or 700-900 picoliters, or 700-800 picoliters, or 800-1000 picoliters, or 800-900 picoliters, or 900-1000 picoliters. The droplet size of individual droplets can be as follows: approximately 100-200 picoliters, or 100-190 picoliters, or 100-180 picoliters, or 100-170 picoliters, or 100-160 picoliters, or 100-150 picoliters, or 100-140 picoliters, or 100-130 picoliters, or 100-120 picoliters, or 100-110 picoliters, or 110-200 picoliters, or 110-19 0 picoliters, or 110-180 picoliters, or 110-170 picoliters, or 110-160 picoliters, or 110-150 picoliters, or 110-140 picoliters, or 110-130 picoliters, or 110-120 picoliters, or 120-200 picoliters, or 120-190 picoliters, or 120-180 picoliters, or 120-170 picoliters, or 120-160 picoliters, or 120-150 picoliters Coliters, or 120-140 picoliters, or 120-130 picoliters, or 130-200 picoliters, or 130-190 picoliters, or 130-180 picoliters, or 130-170 picoliters, or 130-160 picoliters, or 130-150 picoliters, or 130-140 picoliters, or 140-200 picoliters, or 140-190 picoliters, or 140-180 picoliters, or 140-170 picoliters liters, or 140-160 picoliters, or 140-150 picoliters, or 150-200 picoliters, or 150-190 picoliters, or 150-180 picoliters, or 150-170 picoliters, or 150-160 picoliters, or 160-200 picoliters, or 160-190 picoliters, or 160-180 picoliters, or 160-170 picoliters, 170-200 picoliters, or 170-190 picoliters,Or 170-180 picoliters, or 180-200 picoliters, or 180-190 picoliters, or 190-200 picoliters.

[0103] The frequencies for distributing the droplets are as follows: approximately 1 Hz to 1000 Hz, or approximately 1 Hz to 900 Hz, or approximately 1 Hz to 800 Hz, or approximately 1 Hz to 700 Hz, or approximately 1 Hz to 600 Hz, or approximately 1 Hz to 500 Hz, or approximately 1 Hz to 400 Hz, or approximately 1 Hz to 300 Hz, or approximately 1 Hz to 200 Hz, or approximately 1 Hz to 100 Hz, or approximately 1 Hz to 90 Hz, or approximately 1 Hz to 80 Hz, or approximately 1 Hz to 70 Hz, or approximately 1 Hz to 60 Hz, or approximately 1 Hz to 50 Hz, or approximately 1 Hz to approximately 40Hz, or approximately 1Hz to approximately 30Hz, or approximately 1Hz to approximately 20Hz, or approximately 1Hz to approximately 10Hz, or approximately 10Hz to approximately 100Hz, or approximately 10Hz to approximately 90Hz, or approximately 10Hz to approximately 80Hz, or approximately 10Hz to approximately 70Hz, or approximately 10Hz to approximately 60Hz, or approximately 10Hz to approximately 50Hz, or approximately 10Hz to approximately 40Hz, or approximately 10Hz to approximately 30Hz, or approximately 10Hz to approximately 20Hz, or approximately 20Hz to approximately 100Hz, or approximately 20Hz to approximately 90Hz, or approximately 20Hz to approximately 80Hz, or approximately 20Hz to approximately 70 Hz, or approximately 20Hz to 60Hz, or approximately 20Hz to 50Hz, or approximately 20Hz to 40Hz, or approximately 20Hz to 30Hz, or approximately 30Hz to 100Hz, or approximately 30Hz to 90Hz, or approximately 30Hz to 80Hz, or approximately 30Hz to 70Hz, or approximately 30Hz to 60Hz, or approximately 30Hz to 50Hz, or approximately 30Hz to 40Hz, or approximately 40Hz to 100Hz, or approximately 40Hz to 90Hz, or approximately 40Hz to 80Hz, or approximately 40Hz to 70Hz, or approximately 40Hz to 60Hz, Or approximately 40Hz to 50Hz, or approximately 50Hz to 100Hz, or approximately 50Hz to 90Hz, or approximately 50Hz to 80Hz, or approximately 50Hz to 70Hz, or approximately 50Hz to 60Hz, or approximately 60Hz to 100Hz, or approximately 60Hz to 90Hz, or approximately 60Hz to 80Hz, or approximately 60Hz to 70Hz, or approximately 70Hz to 100Hz, or approximately 70Hz to 90Hz, or approximately 70Hz to 80Hz, or approximately 80Hz to 100Hz, or approximately 80Hz to 90Hz, or approximately 90Hz to 100Hz.

[0104] In some cases, burst-mode priming procedures may be performed at higher frequencies, for example, at approximately 1 kHz for 10 bursts. At higher frequencies, such priming modes may be used to re-establish the position and shape of the meniscus.

[0105] Figure 17 shows an embodiment of the printhead of the present invention having one inlet and one outlet, with an upper plate less than 100 μm thick, capable of providing fluid recirculation. The printhead has an upper plate (1711) having a single inlet (1712) and exhaust port (1713). Below the upper plate (1711) is a fluid distribution plate (1714) having a reservoir (1715) for the printing fluid. Below the fluid distribution plate is a piezoelectric device (1716), below which is a piezoelectric film (1717), both located within a piezoelectric film plate (1718). Below the piezoelectric film plate (1718) is a piezoelectric deformation clearance plate (1719), below which is a pump chamber plate (1720). Below the pump chamber plate (1720) is a nozzle plate (1721). The printhead can be filled with fluid using both the inlet and the outlet. The distribution plate can be up to 2 mm thick and provides two reservoirs that help attenuate sound waves transmitted from the pump chamber through the restrictor. The larger the reservoir volume, the better the attenuation and frequency response for maintaining droplet size and droplet velocity. The central ring of the plate should have a diameter at least 1 mm larger than the diameter of the piezo. This is used to hold (clamp) the PZT membrane plate, which has a simply supported beam structure, so that the PZT can still deform. The PZT plate provides acoustic energy for droplet formation. The PZT is actuated by an electrical signal that pushes the membrane, which then generates a pressure change in the fluid beneath the membrane. In a preferred embodiment of the printhead of the present invention, the membrane plate is less than about 100 μm thick. The PZT deformation clearance plate should be about 20-60 μm thick.

[0106] Figures 18A and 18B disclose preferred embodiments of the pump chamber plate of the printhead of the present invention. Figure 18A is a top view of the pump chamber plate, and 18B is a top view of the assembly. Fluid flows in from the fluid inlet (1801) and then through restrictor 1 (1802) into the pump chamber region. After the pump chamber is filled with fluid, the fluid flows through restrictor 2 (1803) to the fluid outlet (1804). The dimensions of the pump chamber must be slightly larger than the dimensions of the nozzle array. As seen in Figure 18B, once the chamber is filled, there are several ventilation devices (1805) surrounding the pump chamber so that each region of the pump chamber has separate conduits (channels) for air to escape. The fluid paths have rounded contours to reduce pressure shock to the pump chamber and to maintain low Reynolds number flow during the process of filling the pump chamber. The sharp edges shown in Figure 18C create fixed points relative to the moving contact line in order to slow down the velocity of the edges of the moving contact line.

[0107] Unlike conventional nozzle plates where all openings are used for droplet formation, the nozzle plate of the present invention can provide vent holes (typically less than 50 μm in diameter) connected to each venting device within the pump chamber plate (Figures 19A and 19B). In preferred embodiments, these vent holes are straight and non-tapering to generate high flow resistance to stop droplet formation during PZT operation. The diameter of the vent holes must be smaller than the diameter of the nozzle holes to prevent leakage. Figures 20A-C show a series of diagrams of chamber filling.

[0108] The pump chamber can be manufactured from a single solid molded body of borosilicate glass or quartz glass. In this way, the minimum number of parts can be used, thus reducing manufacturing costs and complexity. The membrane plate is placed inside the pump chamber and may be manufactured from stainless steel, silicon oxide, and polyimide (Kapton), but is not limited to these. When electrically actuated, the piezoelectric multilayer actuator is mounted in a releasable manner to the membrane plate such that the multilayer presses a membrane onto the fluid in the pump chamber, and nozzles in the nozzle plate distribute droplets of a two-dimensional array onto the micro-protrusions of the micro-protrusion array. The entire apparatus may be enclosed by a housing attached to the pump chamber. To reduce the fluid temperature to 4°C, a cooling device may be incorporated into the housing of the piezoelectric actuator. In an alternative embodiment, the cooling unit may be located outside the pump chamber.

[0109] In addition to maintaining temperature control of the distributed fluid, it is desirable to keep the fluid homogeneous through mixing. Fluid mixing may be achieved by mechanisms including, but not limited to, magnetic agitators, or peristaltic pumps, or microfluidic channels driven by separate PZTs, or a combination thereof.

[0110] In high-speed printing of biological or therapeutic materials (substances), it is desirable to monitor the output so that the amount of material dispensed can be identified in order to ensure the quality of any product manufactured or coated using a high-speed printing apparatus. The ability to monitor the output of a high-speed printing apparatus in real time offers the advantage of saving costs and time. One way to monitor the output from the nozzle is to measure the weight of the material being dispensed. Another method is to measure the resistance of multiple dispenses so that the amount supplied falls within a preset (one or more) dispense parameter. Measuring a single pulse of the piezoelectric unit corresponding to a single droplet is preferable, but it may be necessary to measure multiple dispenses and average the results to determine whether the amount of material being dispensed is accurate. In some embodiments, the number of dispenses measured is 2 to 10, or 2 to 9, or 2 to 8, or 2 to 7, or 2 to 6, or 2 to 5, or 2 to 4, or 2 to 3. In some embodiments, the number of dispenses measured is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20.

[0111] It is desirable to be able to monitor the properties of the fluid being dispensed from a high-speed printing device. For example, monitoring the volume, heterogeneity, pH, protein content, viscosity, or temperature of the fluid at any given time ensures the quality of the material being dispensed.

[0112] [Drop Mass Dispense Check] Confirmation of pharmaceutical dosage is a useful measurement in any coating process. It is desirable to be able to characterize printhead performance to ensure the quality of any product manufactured or coated using high-speed printing equipment. Two predictors of print performance are droplet uniformity and droplet rate. In the printhead of the present invention, periodic checks can be performed to measure the mass of what is dispensed from the printhead and monitor it to ensure that the dispensed amount is within acceptable tolerances. The printhead of the present invention presents a challenge because only small amounts of fluid are dispensed with each operation of the nozzle array (e.g., 1,600 nozzles each eject approximately 150 pL droplets = ~240 nL = ~0.24 mg). Coupled with the relatively high rate of evaporation from the above small droplets (due to surface area), it is difficult to reliably measure the mass. The volume and evaporation problems of small droplets can be overcome by two approaches (as well as a combination of approaches): increasing the mass measured and reducing the effects of evaporation.

[0113] One embodiment involves rapidly distributing more droplets consecutively onto the same substrate (e.g., a different distribution profile than typical patch coating), which increases the drying rate between consecutive drops. Rapidly distributing multiple droplets consecutively leads to droplet aggregation, which reduces the surface area-to-volume ratio and increases mass. The number of droplets to be measured can be selected such that their mass is within a range that can be accurately measured in a manufacturing environment, for example, 18–24°C in a downward laminar flow isolator, and ideally will correspond to the number of droplets intended to be printed on each patch. As an example, to coat 80 μg of tetravalent influenza HA, approximately 21.6 μL of a stock formulation at 3.7 mg / mL would be required. The total liquid distributed would have a mass of approximately 21.6 mg. The volume may also be selected to be larger than that received by a single patch, but is still representative of the average distribution cycle. A range of 10–200 mg can cover the amount of material to be measured.

[0114] A second embodiment aims to further minimize evaporation by introducing a metering check container into a process that may have many properties intended to minimize evaporation. The second embodiment includes, but is not limited to, the use of a) a small container with walls (or a surface with a recess), b) a lid, c) a container with a recessed interior, and d) a container in which the interface between the liquid surface and air is brought very close to the nozzle discharge plate, minimizing the probability that droplets will not be "captured" by the liquid (referred to as the "capture liquid"). The capture liquid in the metering check container may be selected to further reduce the evaporation rate of the material being distributed. Thus, the capture liquid may be, but is not limited to, a) a liquid with a lower density than the distributed liquid (so that it naturally lies on the liquid-gas interface), b) a low vapor pressure under the conditions of the manufacturing environment (temperature and pressure) (to minimize evaporation loss), c) a low surface tension and viscosity (to facilitate drip penetration into the liquid), and d) a suitable level of miscibility with the distributed liquid so that the distributed liquid is quickly captured below the layer of capture liquid. Figure 21 shows one embodiment of the mass inspection function of the instrument of the present invention. The IPC mass container can be positioned below the printhead, as close to the printhead as possible, to minimize material loss due to evaporation. The IPC container can contain a low vapor pressure liquid into which a predetermined amount of coating material can be dispensed from the printhead. Once the printhead material has been dispensed into the low vapor pressure liquid in the IPC container, the container lid is closed and the container is transferred to the weighing station. The next patch tray can then be attached and the coating of the micro-protrusion array can continue. The IPC container is left on the balance for less than 50 seconds, preferably less than 30 seconds, and the IPC container can be removed from the balance and prepared for the next printhead weight inspection. The difference in mass from one weighing to the next provides information about the amount of coating material to be dispensed, so it is not necessary to empty the IPC container.

[0115] Printing a single droplet from each nozzle of a 2D nozzle array onto a hydrophobic surface with a single piezoelectric pulse requires checking the alignment of each nozzle, assuming that the print head is as physically close as possible to the hydrophobic substrate (for example, approximately 100 μm for a droplet diameter of approximately 80 μm) without splitting the droplet. The droplet velocity can be determined by moving the hydrophobic substrate while printing a single pulse array. By printing multiple separated arrays while continuously moving the substrate in an orthogonal direction and comparing the results with those obtained from a static array, the uniformity of the droplet velocity and angle can be evaluated. If the droplet velocity from the nozzle is lower than the predicted velocity, the spacing between droplets will be different. The tolerance can be determined using the above method, and the pass / fail criteria can be applied to the device.

[0116] It is desirable to be able to monitor the properties of the fluid being dispensed from a high-speed printing device. For example, monitoring the volume, heterogeneity, pH, protein content, viscosity, or temperature of the fluid at any given time ensures the quality of the material being dispensed. The above approach regarding droplet weight can be applied to measuring various properties of the solution, as listed above. The properties of the solution can be measured either in-line or offline.

[0117] [Print Hold Function] Coating pharmaceutical or biological materials onto devices such as micro-projection arrays presents unique challenges not encountered in non-sterile environments. Often, pharmaceutical or biological preparations cannot be sterilized and therefore must be manufactured in a sealed and controlled environment. Commercial printheads require regular wiping to clean the head and prevent moisture on the nozzle plate. Alternatively, printheads can be capped to prevent nozzle clogging by dried printer ink when the printing process is stopped. Neither of these processes is desirable in aseptic printing of biological materials, as there is a risk of generating contamination or particles that could clog the nozzles. Cleaning the printhead and using equipment to interrupt printing in a sterile environment would complicate the process and jeopardize product integrity. However, the method of the present invention does not require stopping printing for a period of time. The method of the present invention provides a solution that does not require nozzle wiping or capping and therefore provides a contactless printing or coating method that conforms to aseptic or GMP manufacturing.

[0118] During printhead operation, the nozzle plate is filled with fluid, and a meniscus forms at the nozzle exit due to capillary action and the liquid-gas interface. When exposed to the ambient environment, the solvent in the fluid (e.g., water) evaporates from the meniscus, leaving the solute at the nozzle exit. In a static state where the solvent evaporates, the solute accumulates at the nozzle exit, thereby clogging the exit and impairing its ability to form droplets from the nozzle during the spraying process. In certain industrial processes not based on GMP or sterile conditions, wetting agents may be added to the fluid to allow the solute to remain "soft" even as the solvent evaporates. The addition of wetting agents to pharmaceutical or biological materials is undesirable. It is also possible to activate a piezoelectric mechanism within the printhead to vibrate the meniscus that brings the solvent to the nozzle exit. Doing so refreshes the meniscus and prevents solute accumulation at the nozzle exit. The degree of vibration is influenced by the thickness of the nozzle plate, defined as the distance from the nozzle exit to a first point that is discontinuous with the profile inside the nozzle. Figures 22A, B, and C show three different nozzle shapes, with only Figure 22C having a continuous internal profile. The nozzles in Figures 22A and 22B have nozzle shapes with singularities. Figures 23A and 23B are diagrams of nozzle plates and drop plates with discontinuous and continuous internal profiles, respectively. In the geometry of most commercially available printheads, the continuous nozzle profile is less than 100 μm. As a result, if the meniscus vibration is too high, the meniscus contact line retracts into the internal profile of the nozzle plate, contacts the singularity, and leads to either the cessation or breakdown of the contact line's motion. When the contact line stops at the singularity, the concave meniscus can retract into the nozzle over a long period of time. The nozzle is already closed before the center of the meniscus vibrates back into the nozzle. This can result in air being trapped inside the nozzle, potentially leading to a failure of fluid distribution. When the contact line is broken at the singularity inside the nozzle, a phenomenon called air gulping occurs. A damaged meniscus contact line allows air bubbles to enter the shoulder area above the nozzle, leading to printing defects.Consequently, the spatial design for piezoelectric waveforms is limited by the fact that the resulting meniscus contact line vibration must have low boundary conditions within the thickness of the nozzle plate. In the nozzle plate of the present invention, the nozzle plate can have a thickness of up to 1000 μm, and the nozzle can have a continuous internal profile. This allows the meniscus contact line within the nozzle plate to move up and down in a total travel space of up to 1000 μm without the risk of trapping bubbles (see Figures 24A and 24B).

[0119] The piezoelectric operating waveform generates meniscus oscillation. In one embodiment, a piezoelectric unimorph structure is used to operate a droplet formation process. In this embodiment, the piezo has a capacitive load of approximately 1 to 20 nF and is driven using a waveform with a peak-to-peak (maximum amplitude) voltage of approximately -200 V to +200 V. Figure 25 shows the waveform used to enable meniscus oscillation. Unlike the waveform used to generate droplet formation, the meniscus oscillation waveform does not have high voltages up to +200 V that generate positive pressure in the pump chamber, such as droplet formation. Instead, the meniscus oscillation waveform operates primarily in the negative voltage range to generate a pressure wave at the harmonic frequencies of the meniscus oscillation. Depending on the velocity of sound in the fluid being printed and the geometric shape of the nozzle plate, including its thickness, the waveform can take on different shapes. The frequency at which the waveform shown in Figure 25 operates may be up to 1000 Hz. Another factor to consider in the meniscus oscillation waveform is the slew rate, which is the rate at which the voltage changes from one voltage value to another. In one embodiment of the meniscus oscillation waveform, the slew rate should exceed 150 V / μs. A high slew rate allows for rapid changes in the piezo dimension, resulting in rapid changes in the pump chamber pressure. To achieve a high slew rate for capacitive loads up to 20 nF, the piezo should have the following characteristics: a minimum slew rate of 150 V / μs, a capacitive load up to 20 nF, a peak current of 3 A, an internal waveform frequency of 100 Hz, and a global waveform frequency up to 1000 Hz. In some embodiments of the printing apparatus of the present invention, the thickness of the pump chamber is less than 0.3 mm. A thinner pump chamber provides a smaller pump chamber fluid volume and therefore provides less equivalent fluid capacitance and a faster response to fluid pressure changes.

[0120] In the nozzle plate of the present invention, the nozzle plate can have a thickness of 100 μm, 150 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, or up to 1000 μm. In the nozzle plate of the present invention, the nozzle plate can have the following thicknesses: approximately 100 μm to 1000 μm, or approximately 150 μm to 1000 μm, or approximately 200 μm to 1000 μm, or approximately 250 μm to 1000 μm, or approximately 300 μm to 1000 μm, or approximately 400 μm to 1000 μm, or approximately 500 μm to 1000 μm, or approximately 600 μm to 1000 μm, or approximately 700 μm to 1000 μm, or approximately 800 μm to 1000 μm, or approximately 9 00μm~1000μm, or approximately 100μm~900μm, or approximately 150μm~900μm, or approximately 200μm~900μm, or approximately 250μm~900μm, or approximately 300μm~900μm, or approximately 400μm~900μm, or approximately 500μm~900μm, or approximately 600μm~900μm, or approximately 700μm~900μm, or approximately 800μm~900μm, or approximately 100μm~800μm, or approximately 150μm~800μm, or approximately 200μ m~800μm, or approximately 250μm~800μm, or approximately 300μm~800μm, or approximately 400μm~800μm, or approximately 500μm~800μm, or approximately 600μm~800μm, or approximately 700μm~800μm, or approximately 100μm~700μm, or approximately 150μm~700μm, or approximately 200μm~700μm, or approximately 250μm~700μm, or approximately 300μm~700μm, or approximately 400μm~700μm, or approximately 500μm~70 0 μm, or approximately 600 μm to 700 μm, or approximately 100 μm to 600 μm, or approximately 150 μm to 600 μm, or approximately 200 μm to 600 μm, or approximately 250 μm to 600 μm, or approximately 300 μm to 600 μm, or approximately 400 μm to 600 μm, or approximately 500 μm to 600 μm, or approximately 100 μm to 500 μm, or approximately 150 μm to 500 μm, or approximately 200 μm to 500 μm, or approximately 250 μm to 500 μm, or approximately 300 μm to 500 μmOr approximately 400 μm to 500 μm, or approximately 100 μm to 500 μm, or approximately 150 μm to 500 μm, or approximately 200 μm to 500 μm, or approximately 250 μm to 500 μm, or approximately 500 μm to 600 μm, or approximately 100 μm to 400 μm, or approximately 150 μm to 400 μm, or approximately 200 μm to 400 μm, or approximately 250 μm to 400 μm, or approximately 100 μm to 300 μm, or approximately 150 μm to 300 μm, or approximately 200 μm to 300 μm, or approximately 250 μm to 300 μm, or approximately 100 μm to 200 μm, or approximately 150 μm to 200 μm, or approximately 100 μm to 150 μm. By increasing the nozzle plate thickness, the meniscus retraction and vibration well above the nozzle outlet (the descending portion of the nozzle plate) can be significantly increased without causing problems related to air entrapment. This meniscus retraction and vibration is large enough to enable complete material mixing across the entire liquid-gas interface. Complete material mixing minimizes the chemical potential of all molecules at the liquid-gas interface, making it equal to that of the liquid.

[0121] To prevent the printing material from drying out, the printhead device provides a "tickling" function that changes the piezoelectric waveform to form droplets of the fluid material, but does not eject them from the nozzle. This function can provide a "rebound" of the meniscus layer for a certain period. If the nozzle is cleaned before the next printing cycle, the nozzle shape can be designed so that more complete mixing of the fluid from the droplet meniscus allows for intermittent printing stoppages. The "tickled" fluid can be recirculated within the nozzle shape, and the distribution of fluid from the nozzle can be resumed by returning to the piezoelectric printing waveform.

[0122] The nozzle plate thickness in commercially available printheads is less than 100 μm. The nozzle plate of the present invention can have a thickness of about 50 μm to about 5 mm. Preferably, the nozzle plate is about 200 μm to about 500 μm, or about 250 μm to about 500 μm, or about 300 μm to about 500 μm, or about 350 μm to about 500 μm, or about 400 μm to about 500 μm, or about 450 μm to about 500 μm. By increasing the thickness of the nozzle plate, a high retraction meniscus motion can be generated within the descending portion of the nozzle plate without causing air entrapment. In the apparatus of the present invention with increased nozzle plate thickness, the retraction meniscus motion is large enough to destroy the meniscus contact line in the nozzle, thereby causing complete mixing of the fluid material across the entire meniscus surface. With thin nozzle plates, such as those found in commercially available printheads, it is not possible to completely destroy the contact line. The reason is that this causes air ingestion problems, preventing complete mixing of the fluid material throughout the meniscus. The waveform requires the generation of a negative pressure wave in the pump chamber, and this pressure wave must be at a harmonic frequency of the meniscus oscillation.

[0123] [Landli Print Head] In some applications of the printhead of the present invention, formulations of fluid materials to be coated onto medical devices such as micro-protrusion arrays are expensive, and minimizing material loss during priming and coating is advantageous. Liquid filling systems for syringes have a considerable amount of residual fluid and require a certain level of fluid to maintain the filling, thereby leading to material loss. The apparatus of the present invention is designed so that the apparatus can "run-dry" and thus minimize material loss during the coating process. The printhead apparatus of the present invention provides monitoring of the reflected piezoelectric signal and identification of waveform changes that occur when there is no flow resistance between the piezoelectric and fluid interface. This monitoring and signal identification can detect when the fluid material is being consumed, and thus the print can be stopped. This monitoring and signal identification method may also be used to detect partial or complete blockage of the nozzle plate of the printhead.

[0124] [Manufacturing of print heads / nozzle plates] Currently, commercially available printhead nozzle plates are manufactured using an EDM process. This process provides the nozzle plate with a good finish, a high level of precision, and a nozzle shape with little variation between nozzles. The EDM process is time-consuming and expensive, and is not an efficient method for manufacturing high-quality disposable printheads or nozzle plates. The printhead / nozzle plate of the present invention may consist of two plates with multiple holes laser-perforated and joined together. The upper plate has multiple holes that are larger than the multiple holes of the lower plate. The multiple holes of the upper plate may be on the order of approximately 2 μm to 2000 μm, preferably approximately 100 μm to approximately 250 μm. The lower plate, through which the fluid is ultimately distributed, has multiple holes corresponding to the multiple holes of the upper plate, but the holes are smaller. The multiple holes in the lower plate are approximately 20 μm to 200 μm, or approximately 30 μm to 200 μm, or approximately 40 μm to 200 μm, or approximately 50 μm to 200 μm, or approximately 60 μm to 200 μm, or approximately 70 μm to 200 μm, or approximately 80 μm to 200 μm, or approximately 90 μm to 200 μm, or approximately 100 μm to 200 μm, or approximately 1 The dimensions should be on the order of 10 μm to approximately 200 μm, or approximately 120 μm to approximately 200 μm, or approximately 130 μm to approximately 200 μm, or approximately 140 μm to approximately 200 μm, or approximately 150 μm to approximately 200 μm, or approximately 160 μm to approximately 200 μm, or approximately 170 μm to approximately 200 μm, or approximately 180 μm to approximately 200 μm, or approximately 190 μm to approximately 200 μm. The two plates can be joined together by methods including, but not limited to, epoxy, diffusion bonding, or laser welding, such that the smaller set of holes in the lower plate are centered on the larger set of holes in the upper plate. The alignment and joining of the two plates provides a final shape that allows for flow similar to that obtained with EDM-manufactured nozzle plates, but this method is faster and less expensive. A combination of laser drilling and EDM manufacturing can also be used to form the printhead / nozzle plate of the present invention. Alternatively, a single nozzle plate without a lowering plate may be used.If there is only one plate below the pump chamber plate, it is called the nozzle plate. However, if two plates are used to make the nozzle plate, the upper plate is called the descending plate and the lower plate is called the nozzle plate.

[0125] [Drying priming] Commercial printers are designed to be pre-filled and pre-prepared before shipment or use. Priming can be very complex and may require a degassing and filtration unit or prolonged vacuum. Such methods are unsuitable for pharmaceutical or biological materials, and therefore, a method is preferred that allows priming in a dry, sterile state, minimizes fluid loss, and enables the manufacture of pre-packed sterile units. It is desirable to have a method that allows pharmaceutical or biological fluid material to be filled into a dry, sterile printhead without generating air bubbles that may affect fluid distribution. The printhead can be filled with fluid without pre-priming or degassing. The fluid flows into the dry, sterile printhead and flows automatically without distributing droplets, removing air that may affect droplet formation. This state is maintained throughout the printing period. In a preferred embodiment of the printhead of the present invention, the lower end of the length of the fluid passage inside the printhead is on a scale of less than 0.50 mm. The length of the fluid passage inside the print head may be less than approximately 0.50 mm, or less than approximately 0.45 mm, or less than approximately 0.40 mm, or less than approximately 0.35 mm, or less than approximately 0.30 mm, or less than approximately 0.35 mm, or less than approximately 0.20 mm, or less than approximately 0.15 mm, or less than approximately 0.10 mm, or less than approximately 0.05 mm.The length of the fluid path inside the print head may be as follows: approximately 0.05 to 0.50 mm, or approximately 0.05 to 0.45 mm, or approximately 0.05 to 0.40 mm, or approximately 0.05 to 0.35 mm, or approximately 0.05 to 0.30 mm, or approximately 0.05 to 0.25 mm, or approximately 0.05 to 0.20 mm, or approximately 0.05 to 0.15 mm, or approximately 0.05 to 0.10 mm, or approximately 0.10 to 0.50 mm. , or approximately 0.10~0.45mm, or approximately 0.10~0.40mm, or approximately 0.10~0.35mm, or approximately 0.10~0.30mm, or approximately 0.10~0.25mm, or approximately 0.10~0.20mm, or approximately 0.10~0.15mm, or approximately 0.15~0.50mm, or approximately 0.15~0.45mm, or approximately 0.15~0.40mm, or approximately 0.15~0.35mm, or approximately 0.15~0 0.30mm, or approximately 0.15~0.25mm, or approximately 0.15~0.20mm, or approximately 0.20~0.50mm, or approximately 0.20~0.45mm, or approximately 0.20~0.40mm, or approximately 0.20~0.35mm, or approximately 0.20~0.30mm, or approximately 0.20~0.25mm, or approximately 0.25~0.50mm, or approximately 0.25~0.45mm, or approximately 0.25~0.40mm, or approximately 0 0.25-0.35 mm, or approximately 0.25-0.30 mm, or approximately 0.30-0.50 mm, or approximately 0.30-0.45 mm, or approximately 0.30-0.40 mm, or approximately 0.30-0.35 mm, or approximately 0.35-0.50 mm, or approximately 0.35-0.45 mm, or approximately 0.35-0.40 mm, or approximately 0.40-0.50 mm, or approximately 0.40-0.45 mm, or approximately 0.45-0.50 mm. Capillary forces, not gravity or hydrostatic pressure, govern the wetting behavior of the three-phase interphase (air-liquid-solid) of fluids at these dimensions. Wetting behavior consists of a moving air-liquid-solid contact line. In the ideal case, the contact line moves so that the line does not occupy the entire space of the fluid passage and thus does not capture air. For example, the liquid appears to push out all the air during dry printhead filling. A typical commercially available printhead has one liquid inlet for ink to fill the printhead and multiple outlets for air to escape.These multiple outlets are injection nozzles, each having its own path for connecting to a liquid inlet. The dimensions of the individual fluid passage lengths are on the order of less than 0.5 mm. When back pressure is applied, the fluid is pushed into the printhead inlet, priming the nozzle so that it fills with fluid without creating bubbles in the pump chamber. In the printhead of the present invention, even though the lower limit of the fluid passage length is less than 0.5 mm, the upper limit of the dimension is up to about 20 mm, which is the dimension of the pump chamber. The unidirectional moving contact line in such a high aspect ratio shape is governed by capillary force. In the printhead of the present invention, the fluid flows into the pump chamber from the inlet channels. The number of inlet channels can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. During the formation of the contact line in the pump chamber, depending on the liquid flow rate of each individual channel, the resulting liquid contact line can form any shape. For the same reasons, the pump chamber liquid filling process with moving contact lines does not depend on a specific mechanism but on the random outcome of numerous factors, including channel flow resistance, surface energy heterogeneity, and local surface topography. This problem is complicated in the printhead of the present invention, as the two-dimensional nozzle array has multiple outlet channels connected to the pump chamber. The outlets are designed to facilitate the recirculation of the printing fluid through the pump chamber, facilitate fluid mixing, and reduce the precipitation of any materials dissolved or suspended in the fluid. As a result of this configuration, while the liquid contact line moves through one outlet channel, the outlet channel with the lowest resistance path will be reached before the other outlet channels. The channel reached first allows the fluid to exit the pump chamber through the aforementioned outlet. Consequently, the pump chamber is not completely filled with fluid and has bubbles in the chamber. This problem can be solved by degassing the fluid and recirculating the degassed fluid through the pump chamber to dissolve the trapped bubbles, but this process increases time and cost and increases the complexity of the process and equipment. Furthermore, degassing pharmaceutical or biological materials is undesirable as it can cause decomposition. Applying vacuum to fluids is also an option, but it does not offer simple and inexpensive results.Finally, this problem can be addressed by vacuuming the printhead, but this can lead to the fluid boiling, which is also undesirable. Therefore, in a preferred embodiment of the printhead of the present invention, there is a single channel for the fluid to enter the pump chamber and a single channel for the fluid to exit the pump chamber. Such a design eliminates competition for fluid entering and exiting the pump chamber and results in reduced air entrainment. Furthermore, in a preferred embodiment of the printhead of the present invention, all boundaries of the pump chamber plate around the multiple nozzles, between the inlet and outlet openings of the pump chamber, have multiple vents to prevent stalling of the contact lines.

[0126] [PZT signal generation] The waveform supplied to drive the PZT (piezoelectric resistor) acts on the fluid and determines the characteristics of the distributed fluid droplets. The droplet size is typically 120 pL, and the nozzle array is typically 2,500–7,500 nozzles / cm². 2 The uniformity of the droplets, the shape and size of the droplets, the elimination of satellite (accompanying) droplets, and the ability to manipulate the fluid interface (meniscus), and therefore the ability to stop printing by meniscus vibration, are all controlled by this signal. Two examples of PZT drivers are shown in Figures 26 and 27. A PZT driver based on the Apex Microtechnology PA96 amplifier provides excellent high-speed control of the PZT with a slew rate up to 250 V / μs and a maximum voltage of ±140-150 V. A PZT driver based on the Apex Microtechnology PA96 amplifier offers slightly lower performance in terms of speed and distortion, but has excellent power consumption. The PA79 amplifier cannot supply enough current to drive the piezoelectric element, and therefore the output is amplified by adding a pair of bipolar transistors. This circuit can be miniaturized to have a sufficiently small footprint so that it can be included in the print head assembly.

[0127] [PZT signal feedback] A control signal is generated to drive the PZT and generate droplets at the nozzle interface, and a second return signal waveform is generated when the PZT returns to its resting position. The above waveform can be examined (queried) to determine whether the system is functioning properly. For example, if there is no fluid in the pump chamber, or if trapped air is present, or if the nozzle shuts off monitoring, the return signal can identify the problem and appropriate action can be taken.

[0128] Signal feedback can be achieved using an RLC meter connected directly to the PZT. For example, a 12.5 kHz sine wave can be sent to the PZT. Under such a sine wave, the print head vibrates, generates friction, and loses heat. The PZT itself, as a sensor, senses the heat loss and generates feedback to the RLC meter, i.e., an ESR value. However, if bubbles are present in the pump chamber, the energy loss will be significantly higher. The ESR value will be significantly different with or without bubbles. If the system is a purely capacitive load, the phase shift of the sine wave signal is 90 degrees, but since it is not a purely capacitive load, the above signal is close to 90 degrees. However, if bubbles are present, the above shift will move further away from 90 degrees. Alternatively, a second, smaller-diameter, thinner "sensitive" PZT can be mounted inside a main PZT, which has a donut shape. The inner PZT is not driven but records the return wave profile monitored during a fault condition (see Figure 28).

[0129] Sterility and cleanliness are crucial when using inkjet technology to coat pharmaceutical formulations onto devices such as micro-projection arrays. Therefore, it is essential that each component of the printhead that comes into contact with the pharmaceutical formulation is manufactured from biocompatible and sterilizable materials such as stainless steel, glass, Teflon®, and nylon (but not limited to these). Since biological materials cannot ultimately be sterilized, the final manufacturing process before packaging must be carried out in a controlled, "clean" environment. This takes place within the area of ​​an isolator that provides a high level of environmental control. All equipment within this space must comply with strict manufacturing and regulatory guidelines.

[0130] As described above, the printhead device of the present invention may have one or more disposable components. For example, the printhead device may be configured such that the piezoelectric stacked actuator is reusable, while the pump chamber and / or nozzle plate are disposable. The printhead device may be disposable as a whole. To maintain a sterile environment, the printhead must be pre-primed with a fluid before sterilization, which minimizes the processes required to set up the manufacturing process. The priming fluid may be similar to the printing fluid, except that it does not contain active biological agents (i.e., vaccines). The purpose of the priming fluid is to completely wet the inner surface of the fluid channel and maintain this bubble-free state until the active printing fluid is initiated. One priming fluid that may be used is water for injection (WFI). Sterilization can be carried out in many ways known to those skilled in the art of pharmaceutical sterilization processes. These methods typically include (but are not limited to) gamma irradiation, ethylene oxide, aldehyde-based sterilizers, and vaporized hydrogen peroxide.

[0131] The printhead device of the present invention may be supplied in aseptic packaging. The entire printhead or subassembly of the device may be supplied in aseptic packaging with the printhead filled with priming solution as described above. In a preferred embodiment, the printhead is free of priming solution because it is difficult to ensure complete removal of any residual priming solution before printing. It would also be difficult to determine the effect of any residual priming solution on the distributed formulation. The printhead device is then removed from the package in an aseptic housing. The printhead is mounted in place, and a supply line from the bulk solution supply system is connected to a supply port on the printhead. If a priming solution is used, a purge (removal) cycle can be performed to prime the solution to be delivered to the substrate (e.g., vaccine solution to microprotrusions on a microprotrusion array). In the case of a dry printhead, purging is not required to prime the printer. In other words, to conserve fluid and reduce the risk of mechanical contamination, it is not necessary to spray fluid during the priming process. The test cycle can then be performed by distributing the solution onto a target. A visual system may inspect the test cycle to ensure that alignment and positional tolerances are met. For example, if a printhead is positioned on a non-porous polymer substrate and the printhead is operated 10 times, ideally 10 droplets will be dispensed onto the substrate from each nozzle. Next, a line scanning camera scans the substrate on which the droplets are printed. By analyzing the scanned image, it is possible to identify 1) how many nozzles are firing and 2) positioning errors (x, y, and rotation). The relative position of the line scanning camera and the substrate is calibrated before the process described above. The line scanning camera may be driven by a 1-D translation stage during the scanning process. Once started, the printhead operates continuously with idle dispensing to prevent drying at the nozzle tips. The printhead may perform periodic purge / clean cycles. In normal use, the array of micro-projections to be coated is manufactured in batches.Here, a batch is a single supply lot of a solution material (e.g., vaccine) and a serial number for a printhead used in manufacturing. The printhead may be disposable.

[0132] Figure 29 shows one embodiment of a high-speed single-printhead coating apparatus comprising X and Y stages to which a micro-protrusion array can be attached, a reference camera with LED light, and a Z stage to which a rotating printhead is attached. To ensure stability, the entire apparatus can be mounted on a base (e.g., a granite base). The translational stage is positioned below the coating height to minimize contamination by fine particles generated by the movement of the stage. The positional accuracy of the stage is + / - 1 μm, and the operating speed is 5000 mm / s. 2 With this acceleration, it can move at speeds up to 500 mm / s. The above design is optimized to further reduce the risk of particle interference during the coating process by optimizing the layer airflow.

[0133] While conventional technologies describe MAP (Microwave Application Pattern) designs, current technologies cannot meet the stringent requirements for high-volume production using low-cost, aseptic methods. For example, seasonal influenza vaccination requires a sterile production volume of 50 million units (approximately 23,000 units / hour) over three months. Some innovation is needed to economically meet these figures while ensuring safety and economic viability. This innovation concerns how products are packaged, assembled, and presented in aseptic manufacturing machines, how they are coated quickly and accurately, and generally, more precisely, how waste is generated even in a sterile environment. To coat micro-protrusion arrays in a cost-effective manner, high-volume coating systems provide complete system control and verification of real-time performance for coating a large number of micro-protrusion arrays at high speed. Such high-volume systems require the use of two or more printhead devices. Such high-throughput devices may utilize two, three, four, five, six, seven, eight, nine, ten, or more printheads.

[0134] [Patch alignment] Poor alignment of the target substrate can lead to a lack of substrate effectiveness and waste of coating material. One method for aligning the target substrate, particularly the micro-protrusion array, is to use computer vision, image processing, and custom sorting algorithms to establish positional data for each micro-protrusion on the micro-protrusion array. The acquired data is used by various motor control units to control the precise movement coordinates. The various motor control units use these coordinates to make fine adjustments and orient the micro-protrusion array to maximize coating by the nozzle. These adjustments are specific to each micro-protrusion array, allowing the print head to be orthogonal to each micro-protrusion array on a consistent standard, regardless of any misalignment or rotation that may have occurred when the micro-protrusion array was loaded into the printing machine.

[0135] [Patch Mat] As described above, the apparatus, apparatus, and methods of the present invention need to provide a high-throughput solution for coating and transporting micro-protrusion arrays. This involves having multiple patches to be coated in a format that allows the patches to be easily coated and transported. One way of providing patches in a more commercially production-friendly form is to interconnect individual MAPs (maps) in multiple compact mats that can be stacked to form a single compact mass requiring minimal packaging. The multiple mats can be handled individually in a sterile environment, or more precisely, the mats can be coated as a single unit, thereby providing already aligned MAPs to the print head and minimizing the equipment footprint. This aspect of the present invention provides means for multiple patches to achieve the above in-plane coupling while allowing slight individual free movement of the patches out of plane. The above format allows each patch to be perfectly paired with the coating base. Patches can be individually removed from the mat by a pick-and-place robot. Some embodiments of the mat format provide a design that minimizes the gaps between patches to prevent over-spraying of the print head onto the coating base and further contamination of the next mat.

[0136] The MAP design allows multiple patches to be connected as a single mat of multiple parts, providing the following: The bonding mat allows for the most compact transport volume, reduces the risk of particulate matter generation during transport and handling, eliminates the need for complex support structures and external packing (syringe tabs), the MAP is handled as if manufactured in a mass, as a single mat rather than as individual parts, and the bonding mat structure protects coated mechanical contact parts from contamination by satellite dripping from the print head. Figures 30–34 provide various embodiments of the mat format for patches of the present invention. Figure 30 shows an embodiment having an aggregation design featuring an out-of-plane planar insertion dovetail connector for mat aggregation (binding). Figure 31 shows an embodiment having an aggregation design featuring an out-of-plane planar insertion connector for mat aggregation and a cruciform end spigot for stacking the multiple mats. Figure 32 shows an embodiment having an aggregation design featuring an in-plane friction mat connector for mat aggregation and a cruciform end spigot for stacking the multiple mats. Figure 33 shows an embodiment in which strong aggregation of the above-mentioned mats in a compact stack is achieved with hexagons and multiple spigots. Figure 34 shows an embodiment without guide shafts (spigots) and instead using in-plane friction mating connectors.

[0137] The mat of the present invention may also be formed in a design in which there is no physical interlock between individual patches, but rather multiple patches are simply joined together as shown in Figures 35-37. Multiple patches form multiple tiles that can be stacked to form a very compact block for transport and handling (Figure 37). The final packed form will have molded trays for top and bottom covers, shrink-wrapped in polyethylene or similar material.

[0138] For in-line sterilization, the array can be placed face down and the outer packaging and bottom cover tray can be removed. Once sterilized, the first layer of 100 patches is lifted by a vacuum plate that holds up 100 patches. The vacuum plate is then placed under the printhead with its protrusions facing upward. The patches are presented to the printhead on the vacuum plate with no visible gaps between them, otherwise a disposable tray or cover / liner is required to prevent contamination by "over-spray" contact with the next load to be coated. After coating, the entire vacuum plate with the coated patches can be moved to a quality control station and also moved for insertion into a patch applicator. The patches may be removed by a system of pneumatic pins located under the vacuum plate, which allows the patches to be pushed up from the array in any order. The vacuum tray is then returned for the next pickup. In one embodiment, 10,000 patches are stacked as 100mm squares, with a height of ~300mm.

[0139] [Fluid reservoir] As described above, the need for sterile / sterilized conditions for the biological coating of micro-protrusion arrays is important in the pharmaceutical field. Having a disposable method for supplying fluid to the printhead provides flexibility in providing sterile / sterilized material for coating the micro-protrusion array. In one embodiment, the fluid distributed by the printhead is provided by an integrated supply container or feed container which is part of the printhead device. Alternative embodiments include an external fluid source which is not integrated with the printhead device but rather separate from the device. The fluid can flow from the reservoir to the printhead by various means including a series of tubes.

[0140] The base of the printer body incorporates control software and pressure sensing for fluid control. Power and connection to the main coating and assembly machines can be achieved via springs equipped with electrical contacts.

[0141] The fluid flow from the fluid reservoir to the printhead can be controlled in various ways. In one embodiment, the fluid is controlled by an integrated fluid pump. Figure 38 shows one embodiment of an integrated fluid reservoir connected to the printhead (3830). In this embodiment, the reservoir is a bio-processing bag housed within an injection-molded polymer cover (3831). The fluid level (fluid surface) of the fluid in the bio-processing bag can be viewed through a transparent window (3832) in the cover connecting the bio-processing bag to the printer body. A barcode / ID label (3833) may be attached to the cover so that the unit can be tracked. The printer dock (3834) is part of the final coating and assembly equipment and is the connection point to the printer.

[0142] Figure 39 shows another embodiment of an integrated fluid reservoir without a cover surrounding the fluid reservoir. In this embodiment, the reservoir is a bioprocessing bag (3935) to which a fluid level window (3932) is joined (sealed). In other respects, the same reference numerals as those used in Figure 38 are used to indicate similar features, except that the reference numerals have been increased by 100.

[0143] Figures 40A and 40B show detailed perspective views of this embodiment of the fluid reservoir. The fluid reservoir may have a sterile connector (4041) for connecting the fluid reservoir (4040) to an external fluid source. The reservoir may have a sampling port (4042) from which the fluid can be sampled and a vent (4043). Furthermore, the reservoir (4040) may have a peristaltic recirculation loop (4044) so ​​that the fluid can be recirculated to maintain uniformity. A transparent molded fluid level window (4032) is attached to the reservoir (4040) via a coupling (4036). The transparent molded fluid level window (4032) may have a window for monitoring the fluid level in the reservoir and may have a hole (4037) for easy connection. The window may include a rim (4038) for easy connection to a print head. The reservoir may have pressure control and be able to vent to the ambient atmosphere. The injection-molded body may include integrated electronics, pressure sensors, and firmware.

[0144] In this embodiment, the printer can rotate in both directions, allowing the print head to perform individual alignment for each patch. The connection dock rotates within the mounting arm. Figure 41 is a schematic diagram of one embodiment of an integrated fluid reservoir interfaced to the print head. A magnetic retainer (4151) holds the device in place, and a flow channel (4152) redirects the layered airflow. The printer plate (4153) and nozzle head (4154) are located at the bottom of the device. A communication / electrical port (4155) is provided to supply power to and control the print head. Figure 42 is a schematic diagram of a printer connector (4261) that rotates within the printer mounting arm (4234) to align the print head nozzles with the patches and the X,Y stage. The connector has multiple positioning magnets (4263), an engagement ramp, and a communication / electrical port (4264) to facilitate the connection of the print head, with the magnets and the communication port aligned.

[0145] In another embodiment, the fluid is controlled by a fluid pump housed in a printer mounting arm (4334) that operates a flexible tube (4371) exposed from the printer (Figure 43). Figure 44 shows an embodiment of an external reservoir, which may include an electromagnetic array (4472) for agitating the fluid. Mounting a reusable non-contact pump on the mounting arm is less expensive but less ergonomic than having the pump in the printer's molded body. However, the cost of non-contact pumps, such as peristaltic or solenoid pumps, can be high as disposable items.

[0146] Figure 45 shows a system for controlling the operation of the printhead. In a broad sense, the system includes a disposable printhead system, a jet control system that controls the operation of the printhead, and auxiliary systems such as a computer system that synchronizes the operation of the printhead with the position control of the patch.

[0147] In this example, the printhead system includes a reservoir 4540, such as a bio-processing bag. The reservoir 4540 is connected to the printhead 4530 via a supply line 4571. A recirculation line 4544 is provided to allow the fluid to be recirculated through the reservoir 4540 and to prevent the fluid from stagnating and solidifying.

[0148] The flow through supply lines 4571 and 4544 is induced by a supply pump 4581 and a recirculation pump 4582. The supply pump 4581 and the recirculation pump 4582 are typically peristaltic pumps, including drive and pump wheels, and form part of the injection control system. The supply pump 4581 and the recirculation pump 4582 are driven by signals from their respective pump speed controllers 4583 and 4584. These controllers are then coupled to a microcontroller 4585, which coordinates the operation of the injection control system. The microcontroller 4585 receives multiple pressure sensors from a pressure sensor 4586 in the supply line 4571, which it can use to control the supply pump 4581.

[0149] The microcontroller 4585 is also coupled to a sensor 4587 that senses a barcode / ID label 4533. The barcode / ID label 4533 allows the microcontroller 4585 to identify what it is indicating the fluid being distributed. This is typically used to access control parameters used when controlling the operation of a pump. These control parameters may include, for example, defined recirculation requirements, required pressure, and PZT operating parameters.

[0150] The microcontroller 4585 is coupled to the waveform generator 4588. The waveform generator 4588 generates a drive signal that is amplified by the amplifier 4589 before being applied to the PZT element 4590 to distribute the fluid.

[0151] During operation, signals are received from the auxiliary system, initiating the operation of the microcontroller 4585 and the waveform generator 4588. As a result, once the patch and printhead are correctly aligned, the auxiliary controller can distribute the fluid.

[0152] In a preferred method of controlling fluid from the reservoir, fluid is supplied from the reservoir to the nozzle plate via a supply peristaltic pump or solenoid pump (4581). A pressure sensor (4586) between the nozzle plate and the pump (4581) monitors the fluid pressure to the nozzle plate and interlocks (switches on) the pump (4581) when fluid is needed. The pump is then disengaged (switched off) when a desired limit is reached. The pump may also be used to purge the head, or the pump may generate negative pressure.

[0153] In certain embodiments, mixing is used to maintain fluid homogeneity. In one embodiment, there is a magnetic agitator incorporated into the reservoir (biological processing bag) that is driven by a circular array of electromagnets embedded in the mold printer body. Another mixing method is performed by a recirculation pump (4582). Recirculation pumps are less expensive and a more readily available alternative, as typical agitator options from suppliers are limited to large bag capacities.

[0154] One type of fluid reservoir (4540) is a bio-processing bag that is ventilated to the ambient air through a 0.2 μm filter. In a preferred embodiment, the bio-processing bag has a sampling port. In some embodiments, the reservoir has the following dimensions: pre-filled reservoir - 110 mm wide x 125 mm deep x 250 mm high; remote reservoir - 90 mm in diameter x 97 mm high.

[0155] The advantages of using a fluid reservoir include sterility, ease of use, flexibility, and cost reduction. Printheads pre-filled in bioprocessing bags can be shipped worldwide via cold chain storage. On-site, the outer packaging is removed, the unit is passed through an isolator, the final layer packaging is removed, and the printhead is mounted on a dock fixed to the coating machine. Since the printhead is supplied sterile without a reservoir, the reservoir can be filled sterile at the coating site. Both the reservoir and printhead can be assembled on-site sterile or inside the isolator. The sterile printer may be configured and supplied with multiple supply lines attached to an external supply. The printhead may be brought inside the isolator and into the supply lines connected to a larger bioprocessing source or external tank. Multiple printheads can be connected to the same supply source. Multiple printheads can be used in large-scale coating and assembly machines. Alternatively, a single printhead can be used in smaller desktop units.

[0156] [Manufacturing of devices using print heads] While many embodiments of the present invention relate to the coating of microprotrusions on a microprotrusion array, multiple printheads, printhead devices, and high-throughput devices can be used for a variety of processes, including the coating of objects other than microprotrusion arrays. The printheads of the present invention can be used with coating materials other than biological or pharmaceutical products. Furthermore, the printheads, devices, and instruments of the present invention may be used to manufacture other devices using a variety of materials, including (but not limited to) polymers. The printheads of the present invention can be used to manufacture a microprotrusion array by distributing a polymer into a mold, thereby enabling the manufacture of a microstructure containing the microprotrusion array.

[0157] [coating] In a preferred embodiment, the printhead device of the present invention coats a plurality of microprotrusions of a microprotrusion array with a vaccine antigen formulation. The antigen may be derived from a pathogenic organism. Pathogenic organisms include, but are not limited to, viruses, bacteria, fungal parasites, algae and protozoa and amoebas. Exemplary viruses include those involved in disease. Disease-related viruses include measles, mumps, rubella, polio, hepatitis A, hepatitis B (e.g., GenBank accession number E02707), and hepatitis C virus (e.g., GenBank accession number E06890), other similar pneumonia viruses, influenza, adenoviruses (e.g., types 4 and 7), rabies (e.g., GenBank accession number M34678), yellow fever, Epstein-Barr virus and other herpes viruses such as papillomavirus. This includes, but is not limited to, viruses such as rheuvirus, Ebola virus, influenza virus, Japanese encephalitis (e.g., GenBank accession number E07883), dengue fever (e.g., GenBank accession number M24444), hantavirus, Sendai virus, respiratory syncytial (RS) virus, orthomyxovirus, vesicular virus, stomatitis virus, visnavirus, cytomegalovirus, or human immunodeficiency virus (HIV) (e.g., GenBank accession number U18552). Any suitable antigen derived from such viruses is useful in carrying out the present invention. For example, exemplary retroviral antigens derived from HIV include, but are not limited to, antigens such as the gene products of the gag, pol, and env genes, Nef protein, reverse transcriptase, or other HIV components. Examples useful for describing hepatitis virus antigens include, but are not limited to, antigens such as the S, M, and L proteins of the hepatitis B virus, the pre-S antigen of the hepatitis B virus, or components of other hepatitis viruses (e.g., hepatitis A, hepatitis B, and hepatitis C) (e.g., hepatitis C virus RNA). Examples useful for describing influenza virus antigens include, but are not limited to, antigens such as hemagglutinins and neuraminidases, or other influenza virus components.Exemplary examples of measles virus antigens include, but are not limited to, antigens such as measles virus fusion proteins or other measles virus components. Examples of rubella virus antigens include, but are not limited to, antigens such as proteins El, E2, and other rubella virus components; and rotavirus antigens such as VP7sc and other rotavirus components. Examples of cytomegalovirus antigens include, but are not limited to, antigens such as envelope glycoprotein B and other cytomegalovirus antigen components. Non-exemplary examples of respiratory syncytial (RS) virus antigens include antigens such as RSV fusion proteins, M2 proteins, and other respiratory syncytial virus antigen components. Examples of herpes simplex virus antigens include, but are not limited to, antigens such as immediate initial proteins, glycoprotein D, and other herpes simplex virus antigen components. Non-exemplary examples of varicella-zoster virus antigens include antigens such as 9PI, gpII, and other varicella-zoster virus antigen components. Non-exclusive examples of Japanese encephalitis virus antigens include antigens such as protein E, ME, ME-NS 1, NS1, NS 1-NS2A, 80%E, and other Japanese encephalitis virus antigen components. Representative examples of rabies virus antigens include, but are not limited to, antigens such as rabies glycoprotein, rabies nucleoprotein, and other rabies virus antigen components. Exemplary examples of papillomavirus antigens include, but are not limited to, L1 and L2 capsid proteins, as well as the E6 / E7 antigen associated with cervical cancer (for further examples of viral antigens, see Fundamental Virology, Second Edition, eds., Fields, BN and Knipe, DM, (1991), Raven Press, New York).

[0158] Illustrative examples of fungi are: Acremonium species, Aspergillus species, Basidiobolus species, Bipolaris species, Blastomyces dermatidis, Candida species, Cladophialophora carrionii, Coccoidiodes immitis, Conidiobolus species, Cryptococcus species, Curvularia species, Epidermophyton species, Exophiala jeanselmei, Exserohilum species, Fonsecaea compacta, Fonsecaea pedrosoi, Fusarium oxysporum, Fusarium solani, Geotrichum candidum, Histoplasma capsulatum var., capsulatum, Histoplasma capsulatum var., duboisii, Hortaea werneckii, Lacazia loboi, Lasiodiplodia theobromae, Leptosphaeria senegalensis, Madurella grisea, Madurella mycetomatis, Malassezia furfur, Microsporum species, Neotestudina rosatii, Onychocola canadensis, Paracoccidioides brasiliensis, Phialophora verrucosa, Piedraia hortae, Piedra iahortae, Pityriasis versicolor, Pseudallesheria boydii, Pyrenochaeta romeroi, Rhizopus arrhizus, Scopulariopsis brevicaulis, Scytalidium dimidiatum, Sporothrix schenckii, Trichophyton species, Trichosporon species, Zygomcete fungi, Absidia corymbifera, Rhizomucor pusillus, and Rhizopus arrhizus.Accordingly, typical fungal antigens that can be used in the configuration and method of the present invention include, but are not limited to, Candida fungal antigen components; histoplasmic fungal antigens such as heat shock protein 60 (HSP60) and other tissue plasma fungal antigen components; Cryptococcus fungal antigens such as capsular polysaccharides and other yeast-like incomplete fungal antigen components; coccidia fungal antigens such as globular antigens and other coccidia fungal antigen components; and tinea fungal antigens such as trichophytin and other coccidia fungal antigen components.

[0159] Exemplary examples of bacteria involved in disease include, but are not limited to, diphtheria (e.g., Corynebacterium diphtheria), pertussis (e.g., Bordetella pertussis, GenBank accession number M35274), tetanus (e.g., Clostridium tetani, GenBank accession number M64353), tuberculosis (e.g., Mycobacterium tuberculosis), pneumonia (e.g., Haemophilus influenzae), cholera (e.g., Vibrio cholerae), anthrax (e.g., Bacillus anthracis), typhoid fever, plague, Shigella (e.g., Shigella dysenteriae), botulism (e.g., Clostridium botulinum), salmonellosis (e.g., GenBank accession number L03833), and peptic ulcer (e.g., Helicobacter). Other pathogenic bacteria include Escherichia coli, Clostridium perfringens, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes.Accordingly, bacterial antigens that may be used in the configuration and method of the present invention include, but are not limited to, the following: pertussis bacterial antigens (e.g., pertussis toxin, filamentous hemagglutinin, peltactin, FIM2, FIM3, adenylyl cyclase, and other pertussis bacterial antigenic components); diphtheria bacterial antigens (e.g., diphtheria toxin or toxin-like substances, and other diphtheria bacterial antigenic components); tetanus bacterial antigens (e.g., tetanus toxin or toxin-like substances, and other tetanus bacterial antigenic components); streptococcal antigens (e.g., M protein, and other streptococcal bacterial antigenic components); gram-negative bacilli antigens (e.g., lipopolysaccharide, and other gram-negative bacterial antigenic components); Mycobacterium tuberculosis bacterial antigens (e.g., mycolic acid, heat shock protein 65 (HSP65), 30kDa major secretory protein, antigen 85A, and other mycobacterial antigenic components); Helicobacter Pylori bacterial antigenic components, pneumocactic bacterial antigens (e.g., pneumocysin, pneumococcal capsular polysaccharides, and other pneumococcal antigenic components); Haemophilus influenzae bacterial antigens (e.g., capsular polysaccharides, and other Haemophilus influenzae bacterial antigenic components); anthraxinus antigens (e.g., anthrax protective antigens, and other anthraxinus antigenic components); and Rickettsiae bacterial antigens (e.g., Rickettsia rompA, and other Rickettsiae bacterial antigenic components). The bacterial antigens described herein also include any other bacteria (mycobacteria, mycoplasma, rickettsia, or chlamydia antigens).

[0160] Exemplary examples of protozoa, including those involved in disease, include, but are not limited to, malaria (e.g., GenBank accession number X53832), hookworm, onchocerciasis (e.g., GenBank accession number M27807), schistosomiasis (e.g., GenBank accession number LOS198), toxoplasmosis, trypanosomiasis, leishmaniasis, giardiasis (GenBank accession number M33641), amoebiasis, filariasis (e.g., GenBank accession number J03266), borreliosis, and trichinellosis. Accordingly, the protozoan antigens that may be used in the configuration and methods of the present invention include, but are not limited to, the following: Plasmodium malariae antigens (e.g., merozoite surface antigen, sporozoite surface antigen, perisporozoite antigen, gamete cell / gamete surface antigen, blood stage antigen pf155 / RESA, and other plasmodial antigen components); Toxoplasma protozoan antigens (e.g., SAG-1, p30, and other toxoplasma antigen components); Schistosomiasis antigens (e.g., glutathione-S-transferase, paramyosin, and other schistosomiasis antigen components); Leishmania major antigen and other Leishmania antigens (e.g., gp63, lipophosphoglycan and its related proteins, and other Leishmania antigen components); Trypanosoma cruzi antigens (e.g., 75-77kDa antigen, 56kDa antigen, and other Trypanosoma antigen components).

[0161] Printhead devices and methods of using printhead devices involve the use of printhead devices, such as depositing a material, such as a polymer, into a mold for the manufacture of various devices including micro-protrusion arrays. In one embodiment of the present invention, the printhead of the present invention can deposit a polymer or other material into a pre-formed mold having depressions. The polymer material can be dispensed from the printhead into the mold to form a micro-protrusion array. The polymer material includes, but is not limited to, all thermoplastics and thermosetting polymers (e.g., polystyrene, polyvinyl chloride, polymethyl methacrylate, acrylonitrile-butadiene styrene, and polycarbonate, as well as polypropylene, polybutylene terephthalate, polystyrene, polyethylene, polythermide, polyethylene terephthalate, and mixtures thereof).

[0162] Any indication within the scope of this disclosure that a feature is optional is intended to provide appropriate support for the claims, including closed language, exclusive language, or negative language, by reference to any feature (e.g., under 35 U.S. SC112 or Art. 83 and 84 of the EPC). Exclusive language excludes, in particular, that a particular enumerated feature includes any additional subject matter. For example, where it is indicated that A may be drug X, such language is intended to support a claim that expressly specifies that A consists only of X, or a claim that expressly specifies that A does not contain any other drug other than X. Negative language expressly excludes any feature itself from the scope of the claims. For example, where it is indicated that element A may contain X, such language is intended to support a claim that expressly specifies that A does not contain X. Non-exclusive examples of exclusive or negative terms include "only," "solely," "consisting of," "consisting essentially of," "alone," "without," "in the absence of (e.g., other items of the same type, structure, and / or function)," "excluding," "not including," "not," "cannot," or any combination and / or variation of such language.

[0163] Similarly, referents such as "a," "an," "said," or "the" are intended to support both singular and / or plural existences unless the context indicates otherwise. For example, "a dog" is intended to support one dog, one or fewer dogs, at least one dog, and more dogs. Non-restrictive examples of appropriate terms for singular include "a single," "one," "alone," "only one," and "not more than one." Non-restrictive examples of appropriate terms for plural (potentially or actually) include "at least one," "one or more," "more than one," "two or more," "a multiplicity," "a plurality," "any combination of," "any permutation of," and "any one or more of." Any claim or description containing "or" among one or more members of a group is considered satisfied if one, one or more, or all members of the group are present in, used in, or otherwise relevant to a given product or process, unless it is shown to be contrary or otherwise obvious from the context.

[0164] Where a range is given herein, it includes the endpoint. Furthermore, unless otherwise indicated or otherwise evident from the context and the understanding of those skilled in the art, the values ​​expressed as a range may, in various embodiments of the invention, be understood to mean any specific value or partial range within the range described, up to one-tenth of the lower limit of that range, unless the context explicitly indicates otherwise.

[0165] Just as each publication or patent is specifically and individually incorporated by reference, all publications and patents cited herein are incorporated herein by reference. Any reference to a publication is for its disclosure prior to the filing date and should not be construed as an acceptance that the present invention is not entitled by the effect of the prior art to date such publication earlier than it actually is.

[0166] Although the present invention has been specifically shown and described with reference to its exemplary embodiments, it will be understood by those skilled in the art that various modifications in form and detail can be made therein without departing from the scope of the invention as encompassed by the appended claims.

[0167] Throughout this specification and the following claims, unless the context requires otherwise, the word “comprise,” and variations such as “comprises,” and “comprising,” shall be understood to mean the inclusion of the integer, group of integers, or process described, but not the exclusion of any other integer or group of integers. As used herein, and unless otherwise specified, the term “about” means ±20%.

[0168] It should be noted that, as used in the specification and the attached claims, the singular forms "a," "an," and "the" include multiple references unless the context explicitly indicates otherwise. Therefore, for example, a reference to "a support" includes multiple supports. In this specification and the following claims, numerous terms are referenced that are defined to have the following meanings, unless otherwise clearly intended.

[0169] Naturally, the above are given as exemplary examples of the present invention, but as will be apparent to those skilled in the art, other modifications and variations are also considered to fall within the broad scope and range of the present invention as described herein.

Claims

1. A device for coating a substrate, a) A piezoelectric actuator and b) Membrane plate and, c) Deformable clearance plate and, d) Restrictor pump room and e) A device comprising a nozzle plate.

2. The apparatus according to claim 1, wherein the piezoelectric actuator is actuated by a signal and is operably connected to the membrane plate, and when the piezoelectric actuator is actuated by the signal, the membrane plate is deformed via the deformation clearance plate, the membrane plate comes into contact with the fluid in the restrictor pump chamber, the fluid is pushed out of the restrictor pump chamber and pushed onto the substrate via a plurality of nozzles of the nozzle plate.

3. The apparatus according to claim 1 or 2, wherein the piezoelectric device is joined to the film plate to form a first subassembly, the deformation clearance plate, the restrictor pump chamber, and the nozzle plate are joined to each other to form a second subassembly, and the first subassembly and the second subassembly are joined to each other to form the apparatus.

4. The piezoelectric actuator is a) Piezoelectric multilayer actuator and b) Piezoelectric Unimorph Actuator The apparatus according to any one of claims 1 to 3, wherein at least one of the above.

5. The apparatus according to any one of claims 1 to 4, further comprising a housing that accommodates the piezoelectric actuator, a membrane plate, a deformation clearance plate, a restrictor pump chamber, and a nozzle plate.

6. The apparatus according to any one of claims 1 to 5, wherein the pump chamber plate is provided with a fluid inlet and a fluid outlet.

7. The apparatus according to any one of claims 1 to 6, wherein the pump chamber plate further comprises one or more restrictors.

8. The apparatus according to any one of claims 1 to 7, wherein the pump room plate further comprises one or more ventilation devices.

9. The apparatus according to any one of claims 1 to 8, wherein the film plate has a thickness of approximately 100 μm or less.

10. The apparatus according to any one of claims 1 to 9, wherein the deformation clearance plate has a thickness of approximately 20 μm to approximately 60 μm.

11. The apparatus according to any one of claims 1 to 10, wherein the nozzle plate includes a plurality of nozzle plate holes, and fluid is distributed from the plurality of nozzle plate holes.

12. The apparatus according to any one of claims 1 to 11, wherein the nozzle plate comprises a plurality of nozzles formed in a two-dimensional array.

13. The apparatus according to claim 12, wherein the number of nozzles in the two-dimensional array is 500 to 5000.

14. The apparatus according to claim 12 or 13, wherein the number of nozzles in each dimension is the same.

15. The apparatus according to any one of claims 1 to 14, wherein the distance between nozzles on the nozzle plate is approximately 50 to approximately 500 micrometers.

16. The apparatus according to any one of claims 1 to 15, wherein the nozzle plate is provided with a plurality of ventilation holes.

17. The apparatus according to claim 16, wherein the plurality of ventilation holes have a diameter of less than 50 μm.

18. The apparatus according to any one of claims 16 to 17, wherein the plurality of ventilation holes are not tapered, and the plurality of ventilation holes generate high flow resistance.

19. The apparatus according to any one of claims 16 to 18, wherein the plurality of ventilation holes have a smaller diameter than the nozzle holes.

20. The apparatus according to any one of claims 1 to 19, wherein the apparatus further comprises a fluid reservoir.

21. The apparatus according to claim 20, wherein the fluid reservoir is integrated with the apparatus.

22. The apparatus according to claim 20, wherein the fluid reservoir is located away from the apparatus.

23. The apparatus according to any one of claims 20 to 22, wherein the fluid reservoir is a bioprocessing bag.

24. The apparatus according to any one of claims 1 to 23, wherein the apparatus further includes means for mixing fluids.

25. The apparatus according to claim 24, wherein the means for mixing the fluid is comprised of an electromagnet.

26. A method for coating a substrate, a) A step of supplying fluid to the pump room, b) A step of activating a piezoelectric device, thereby deforming the membrane plate via the deformation clearance plate, causing the membrane plate to come into contact with the fluid in the pump chamber, and pushing the fluid onto the substrate via a nozzle plate equipped with multiple nozzles, A method that includes this.

27. The method according to claim 26, wherein the substrate is an array of micro-protrusions.

28. The method according to claim 27, wherein the array of microprotrusions comprises two or more microprotrusions, and the fluid coats at least a portion of one or more microprotrusions.

29. The method according to claim 28, wherein the fluid coats the upper half of the plurality of minute protrusions.

30. The method according to any one of claims 26 to 29, wherein the coating fluid is provided by a fluid reservoir.

31. The method according to any one of claims 26 to 30, wherein the plurality of nozzles are made in a two-dimensional array.

32. The method according to claim 31, wherein the number of nozzles in the two-dimensional array is 500 to 5000 nozzles.

33. The method according to claim 31 or 32, wherein the number of nozzles in each dimension is the same.

34. The method according to any one of claims 26 to 33, wherein the distance between the plurality of nozzles is about 50 to about 500 micrometers.

35. The method according to any one of claims 26 to 34, wherein each nozzle distributes approximately 100 to 1000 picoliters of fluid.

36. The method according to any one of claims 26 to 35, wherein the number of nozzles in the nozzle plate is the same as the number of microprotrusions on the microprotrusion array.

37. A device for coating a substrate, a) A pump chamber in which the fluid is contained, b) A nozzle plate attached to the pump chamber, comprising a nozzle plate having a plurality of nozzles for distributing fluid, c) Membrane plate and, d) A piezoelectric actuator comprising a piezoelectric actuator that pushes a membrane plate so that a fluid is distributed through the plurality of nozzles, A device equipped with the following features.

38. The piezoelectric actuator is a) Piezoelectric multilayer actuator and b) Piezoelectric unimorph actuator and The apparatus according to claim 37, wherein at least one of the following is present.

39. The apparatus according to any one of claims 37 to 38, further comprising an apparatus for mixing the aforementioned fluid.

40. The apparatus according to any one of claims 37 to 39, further comprising a housing.

41. The apparatus according to claim 40, wherein the housing includes a cooling device.

42. The apparatus according to any one of claims 37 to 41, wherein the nozzle plate further comprises one or more fluid ports through which the fluid is pushed into the pump chamber.

43. The apparatus according to claim 42, wherein the nozzle plate has two fluid ports.

44. The aforementioned plurality of nozzles are a) Etched silicon and b) Electroformed nickel and The apparatus according to any one of claims 37 to 43, manufactured from at least one of the following.

45. The apparatus according to any one of claims 37 to 44, wherein the plurality of nozzles are manufactured in a two-dimensional array.

46. The apparatus according to claim 45, wherein the number of nozzles in the two-dimensional array is 500 to 5000.

47. The apparatus according to claim 45 or 46, wherein the number of nozzles in each dimension is the same.

48. The apparatus according to any one of claims 37 to 47, wherein the distance between nozzles is approximately 50 to approximately 500 micrometers.

49. The apparatus according to any one of claims 37 to 48, wherein each nozzle distributes approximately 100 to 1000 picoliters of fluid.

50. The aforementioned plurality of nozzles are a) Durability and, b) Hydrophobic and, The apparatus according to any one of claims 37 to 49, which is coated to enhance at least one of the following.

51. The apparatus according to any one of claims 1 to 25 or 37 to 50, wherein the fluid is a biological substance.

52. The apparatus according to claim 51, wherein the fluid is a vaccine.

53. The apparatus according to any one of claims 1 to 25 or 37 to 52, wherein the pump chamber is molded.

54. The apparatus according to any one of claims 1 to 25 or 37 to 53, wherein the apparatus is pre-primed with a priming solution.

55. The apparatus according to any one of claims 1 to 25 or 37 to 54, wherein the membrane plate is made of stainless steel.

56. The apparatus according to any one of claims 1 to 25 or 37 to 55, wherein the apparatus is sterile.

57. The apparatus according to any one of claims 1 to 25 or 37 to 56, wherein the plurality of nozzles are sterile.

58. The apparatus according to any one of claims 1 to 25 or 37 to 57, wherein the apparatus is disposable.

59. The apparatus according to any one of claims 1 to 25 or 37 to 58, wherein the nozzle plate is disposable.

60. The apparatus according to any one of claims 1 to 25 or 37 to 59, wherein the restrictor pump chamber is disposable.

61. The apparatus according to any one of claims 1 to 25 or 37 to 60, wherein the apparatus is for coating the substrate with a biological fluid, and the biological fluid is kept in a sterile state.

62. The apparatus according to any one of claims 1 to 25 or 37 to 61, wherein the apparatus is for coating the substrate with a vaccine, and the vaccine is kept in a sterile state.

63. A method for coating a microprotrusion array, a) The step of aligning the apparatus according to any one of claims 1 to 25 or 37 to 62 on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a microprotrusion, b) The steps of operating the actuator so that the membrane plate pushes fluid through the plurality of nozzles onto the plurality of micro-protrusions, thereby coating the array of micro-protrusions, A method that includes this.

64. A method for coating microprotrusions on a microprotrusion array up to a predetermined volume, a) The step of aligning the apparatus according to any one of claims 1 to 25 or 37 to 62 on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a microprotrusion, b) The step of operating the actuator so that the membrane plate pushes fluid through the plurality of nozzles onto the plurality of micro-protrusions, c) A step of repeating step (b) to coat the plurality of minute protrusions to a predetermined volume, A method that includes this.

65. A method for coating microprotrusions on a microprotrusion array, a) Aligning the apparatus according to any one of claims 1 to 25 or 37 to 62 on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a first set of uncoated microprotrusions, b) The actuator is activated so that the membrane plate pushes fluid through the plurality of nozzles onto the first set of micro-protrusions, thereby coating the micro-protrusions. c) Moving the array of micro-protrusions relative to the apparatus so that the plurality of nozzles align on a second set of uncoated micro-protrusions, d) The actuator is activated so that the membrane plate pushes fluid through the plurality of nozzles onto the second set of micro-protrusions, thereby coating the micro-protrusions. A method that includes this.

66. The method according to any one of claims 63 to 65, wherein the method includes aligning the plurality of nozzles to a distance of about 50 to about 500 micrometers from the plurality of microprotrusions.

67. The method according to any one of claims 63 to 66, wherein the alignment of the device on the array of micro-protrusions is achieved by using a camera.

68. A method for coating microprotrusions on a microprotrusion array, a) Aligning the apparatus according to any one of claims 1 to 25 or 37 to 62 on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a first set of uncoated microprotrusions, b) The step of operating the actuator so that the membrane plate pushes a first fluid through the plurality of nozzles onto the first set of micro-protrusions, thereby coating the plurality of micro-protrusions, c) Move the array of micro-protrusions relative to the apparatus so that the plurality of nozzles are aligned on a second set of uncoated micro-protrusions, d) The step of operating the actuator so that the membrane plate pushes a second fluid through the plurality of nozzles onto the second set of micro-protrusions, thereby coating the plurality of micro-protrusions, A method that includes this.

69. A method for coating microprotrusions on a microprotrusion array, a) The step of aligning the apparatus according to any one of claims 1 to 25 or 37 to 62 on a microprotrusion array including a plurality of microprotrusions such that each nozzle aligns on a microprotrusion, b) The step of operating the actuator so that the membrane plate pushes the first fluid through the plurality of nozzles onto the plurality of micro-protrusions, c) The step of operating the actuator so that the membrane plate pushes the second fluid through the plurality of nozzles onto the plurality of micro-protrusions, A method that includes this.

70. A device for coating one or more microprotrusions on a microprotrusion array, a) Housing and b) Piezoelectric actuator and c) Restrictor plate and, d) Membrane plate and e) Pump room and, f) Descending plate and, g) Including a nozzle plate, The device is such that the piezoelectric stacked actuator is movably connected to the film plate such that when the piezoelectric stacked actuator is operated, the piezoelectric stacked actuator presses against the film plate.

71. The apparatus according to claim 70, further comprising one or more ports attached to the pump chamber.

72. The apparatus according to claim 70 or 71, further comprising a second restrictor plate.

73. A device for coating one or more microprotrusions on a microprotrusion array, It comprises a housing connected to a pump chamber, which is attached to a lowering plate that is attached to a nozzle plate, The apparatus includes a piezoelectric unimorph actuator operably connected to the membrane plate between the housing and the pump chamber, such that when the piezoelectric laminated actuator is operated, the piezoelectric laminated actuator pushes the membrane plate.

74. The apparatus according to claim 73, further comprising one or more ports attached to the pump chamber.

75. The apparatus according to claim 73 or 74, further comprising a second restrictor plate.

76. A device for printing material onto a substrate, a) A top plate including a single inlet hole and a single outlet hole that are detachably connected, b) A fluid distribution plate including one or more reservoirs that are detachably connected, c) A piezoelectric device and a piezoelectric film plate including a film beneath the piezoelectric device, wherein the film deforms when the piezoelectric device is operated, and the piezoelectric film plate is reattachably connected, d) A piezoelectric deformation clearance plate that is reattachable and connected, e) A pump chamber plate that is reattachable and connected, f) A nozzle plate including a plurality of nozzles capable of dispensing a fluid material onto the substrate.

77. The apparatus according to claim 76, wherein the upper plate, fluid distribution plate, piezoelectric film plate, piezoelectric deformation clearance plate, pump chamber plate, and nozzle plate are all housed within the housing.

78. The apparatus according to claim 76 or 77, wherein the nozzle plate has a thickness of approximately 400 to 500 μm.

79. The apparatus according to any one of claims 76 to 78, wherein the pump chamber has a thickness of less than 0.3 mm.

80. The apparatus according to any one of claims 76 to 79, wherein the nozzle geometric shapes of the plurality of nozzles in the nozzle plate are continuous and have no singularities.

81. The apparatus according to any one of claims 76 to 80, wherein the pump chamber plate has a plurality of ventilation holes.

82. The apparatus according to any one of claims 76 to 81, wherein the nozzle plate has a plurality of ventilation holes.

83. The apparatus according to claim 82, wherein the plurality of nozzle plate vent holes are connected to a plurality of pump chamber vent holes.

84. The apparatus according to any one of claims 81 to 83, wherein the plurality of ventilation holes have a diameter of less than 50 μm.

85. The apparatus according to any one of claims 76 to 84, wherein the pump chamber plate has two restrictors.

86. The apparatus according to any one of claims 76 to 85, wherein the nozzle plate comprises two plates, including a lowering plate.

87. A single printhead coating apparatus, a) X, Y translation stage to which a micro-protrusion array can be attached, b) A reference camera with LED lighting, c) A Z-stage with a rotary print head attached, A print head coating device equipped with the following features.

88. The print head coating apparatus according to claim 87, further comprising a base to which the aforementioned stage is attached.

89. The print head coating apparatus according to claim 87 or 88, wherein the translational stage has a positional accuracy of ±1 μm.

90. The print head coating apparatus according to any one of claims 87 to 89, wherein the translational stage can move at a speed of up to 500 mm / s.

91. The aforementioned translation stage operates at 5000 mm / s ２ A print head coating apparatus according to any one of claims 87 to 90, having an acceleration up to [a certain point].

92. A device for coating a substrate, a) A restrictor pump chamber for containing the fluid, b) A nozzle configuration including a plurality of nozzles that are in fluid communication with the restrictor pump chamber, c) Piezoelectric actuator and d) A membrane provided adjacent to the piezoelectric actuator and spaced apart from the restrictor pump chamber, such that the operation of the piezoelectric actuator causes the membrane to come into contact with the fluid in the restrictor pump chamber, thereby driving the fluid into the plurality of nozzles, and thereby injecting the coating solution onto the substrate, A device equipped with the following features.

93. The apparatus according to claim 92, wherein the apparatus is the apparatus according to any one of claims 1 to 25, 37 to 62, and 70 to 86.

94. A device for coating a substrate, a) A restrictor pump chamber for containing the coating solution, b) A nozzle configuration including a plurality of nozzles that are in fluid communication with the restrictor pump chamber, c) Piezoelectric actuator and d) A membrane provided adjacent to the piezoelectric actuator and separated from the restrictor pump chamber by a deformable clearance plate, such that the operation of the piezoelectric actuator causes the membrane to come into pressurized contact with the coating solution in the restrictor pump chamber, thereby driving the coating solution into the plurality of nozzles, and thereby injecting the coating solution onto the substrate, A device equipped with the following features.

95. A method for verifying the mass of a material distributed by the apparatus described in claim 1, a) The step of placing a measuring container near the nozzle plate of the apparatus according to claim 1, b) A step of collecting one or more droplets from one or more nozzles into the container and weighing the one or more droplets, A method that includes this.

96. The method according to claim 95, wherein the measuring container contains a capture liquid, the capture liquid having a lower density, lower vapor pressure, lower surface tension and viscosity than the droplet, and having an appropriate level of miscibility with the dispensed liquid so that the droplet is quickly captured beneath the layer of the capture liquid.

97. A method for coating a substrate, a) A step of supplying fluid from the reservoir to the pump chamber via a microfluidic conduit, b) A step of activating a piezoelectric actuator with an electric drive signal, thereby causing the activated piezoelectric actuator to push a membrane plate, generating a positive pressure wave in the pump chamber toward the nozzle outlet, forming droplets at the nozzle outlet, and causing multiple droplets to exit the nozzle toward the substrate at a speed exceeding 1 m / s, A method that includes this.

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