A nebulizer aperture plate and method of manufacture

Abstract

An aperture plate is for a nebulizer and has an inlet layer (100) with an array of reservoir holes (101), and an outlet layer (200) bonded to the inlet layer and having an array of aerosol-forming apertures (201) in the bases of the inlet layer reservoir holes (101). The layers are in one example of stainless steel and are diffusion bonded to provide a structure which is akin to an integral structure, suitable for high frequency nebulizer operation. The holes in either layer may be provided by laser drilling. The inlet layer is optimized for reinforcement and structural strength of the aperture plate under high frequency vibration, whereas the outlet layer is optimized for formation of desired aerosol droplets. The inlet layer forms a reinforcing structure during laser drilling of the apertures in the outlet layer, through the inlet layer reservoir apertures.

Description

[0001] “A Nebulizer Aperture Plate and Method of Manufacture”

[0002] Introduction

[0003] The invention relates to manufacture of aperture plates (or “vibrating membranes”) for aerosol generation, especially for vibrating mesh atomisers devices for pulmonary treatment. However, it may be applied to other situations such as humidification, spray coating, spin-spray deposition of thin films, spray drying, mass spectrometry, liquid fuel, spray cooling, inkjet printing, 3D prototyping, soft robotic actuation and moisture removal.

[0004] An objective is to achieve a consistent and accurate aerosol parti cl e / droplet size together with an output rate that can be varied according to the application such as delivery of a drug to a targeted lung area as efficiently as possible. For example, delivery of the aerosol to the deep lung such as the bronchi, bronchiole and alveolar regions requires a small and repeatable particle size typically in the range of 1 - 5 pm, but it could be larger for other applications such as humidification. In general, outputs greater than 0.1 ml / min are often required.

[0005] Currently, aperture plates are produced by a variety of different means, including electroforming and machining such as laser drilling. US 6,235,177 (Aerogen) describes an approach based on electroforming, in which a wafer material is built onto a mandrel by a process of electro-deposition where the liquefied metals in the plating bath (typically Palladium and Nickel) are transferred from the liquid form to the solid form on the wafer. Material is transferred to the conducting surface on the mandrel and not to the photo resist areas which are non-conducting. Areas are masked with non-conductive photo resist where metallic build-up is not required. After the conclusion of the plating process, the mandrel / wafer assembly is removed from the bath and the wafer peeled from the mandrel for subsequent processing into an aperture plate. However, a problem with this approach is that the hole size is dependent on the plating time and the thickness of the resulting wafer.

[0006] W02013 / 186031 (Stamford Devices Limited) describes an approach in which a photoresist is applied in a pattern of vertical columns in one phase to provide aerosol-forming apertures and in a second phase to provide liquid supply cavities. The latter provide a reservoir layer of liquid supply cavities. WO2011 / 139233 (Agency for Science, Technology and Research) describes a micro sieve manufactured using SU8 material with photo-masking.

[0007] US4844778 (Stork Veco) describes manufacture of a membrane for separating media, and a separation device incorporating such a membrane. The manufacturing method includes a two-step photolithographic procedure. US7316067 (The Technology Partnership) describes an approach which involves laser drilling of the aerosol-forming apertures. WOOO / 29167 (Aradigm) also describes such an approach. EP3024589 (Philips) describes an approach in which there are two portions of material, in which a first portion for inlet flow has a higher density than the second portion which forms nozzles for an outlet side. EP3793746 (Philip Morris) describes a two-layer mesh element for an atomiser assembly. US2020 / 0094268 (Sall et al) describes manufacture of a nozzle device in which a sieve side membrane is formed by providing a layer onto a first wafer, and a spray side membrane is formed by providing a layer onto a second wafer, and the wafers are bonded. US2013 / 112770 (HSIEH SHU-PIN) describes a nebulization structure with a structure plate and a nebulization plate clamped together. US2017 / 0350030 (Xu) describes patterned photolithography manufacture of an aperture plate by successive masking and plating exposed seed layer surfaces. US2018 / 326726 (WANG XI) describes coating of surfaces of medical or printing devices

[0008] Laser drilling requires the removal of large volumes of material, which must be ablated quickly to minimise the laser machining time for a single aperture plate. The speed and volume of material removed using the laser machining process generates heat and can cause distortion of the wafer with subsequent variability in quality and shape of the exit holes and leading to poor consistency and low yield.

[0009] The invention is directed towards providing an improved method for manufacture of an aperture plate for aerosolization, especially where it is desired to have a reservoir layer, and especially for nebulizers.

[0010] Non-Patent References

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[0031] Summary of the Invention

[0032] We describe an aperture plate for aerosolization, the aperture plate comprising: an inlet layer having an array of reservoir apertures, and an outlet layer bonded to the inlet layer and having an array of aerosol-forming apertures, in which at least some of the reservoir apertures are each in fluid communication with a plurality of aerosol-forming apertures. In some preferred examples, the aperture plate is a nebulizer aperture plate, for generating aerosol droplets for inhalation.

[0033] In some preferred examples, the layers are directly bonded together. In some preferred examples, layers are diffusion bonded together.

[0034] In some preferred examples, at least one of the layers is of a metal alloy, optionally Palladium- Nickel or Hastelloy C276 or Stainless Steel 316L.

[0035] In some preferred examples, both the inlet layer and the outlet layer are of a metal alloy. In some preferred examples, one or both of the layers are of steel material, optionally stainless steel such as Hastelloy. In some preferred examples, the inlet layer and the outlet layer are of a stainless steel material and they are diffusion bonded together.

[0036] In some preferred examples, the inlet layer has a thickness in the range of 10 pm to 2000 pm. In some preferred examples, the inlet layer has a thickness in the range of 20 pm to 200 pm. In some preferred examples, the inlet layer has a thickness in the range of 30 pm to 100 pm.

[0037] In some preferred examples, the reservoir apertures in the inlet layer have a diameter in the range of 10 pm to 200 pm. In some preferred examples, the reservoir apertures in the inlet layer have a diameter in the range of 20 pm to 100 pm. In some preferred examples, the reservoir apertures in the inlet layer have a diameter in the range of 30 pm to 80 pm.

[0038] In some preferred examples, the reservoir aperture pitch is in the range of 30 pm to 300 pm. In some preferred examples, the reservoir hole pitch is in the range of 40 pm to 200 pm. In some preferred examples, the reservoir hole pitch is in the range of 50 pm to 150 pm.

[0039] In some preferred examples, the outlet layer has a thickness in the range of 3 pm to 12 pm. In some preferred examples, the outlet layer has a thickness in the range of 4 pm to 10 pm.

[0040] In some preferred examples, the outlet layer aerosol forming apertures have a diameter in the range of 0.5 pm to 20 pm. In some preferred examples, the outlet layer aerosol forming apertures have a diameter in the range of 1 pm to 6 pm. In some preferred examples, the outlet layer aerosol forming apertures have a diameter on the outlet side in the range of 1.5 pm to 4.5 pm. In some preferred examples, the outlet layer aerosol forming apertures have a diameter on the outlet side in the range of 2 pm to 4 pm.

[0041] In some preferred examples, the outlet layer aerosol forming apertures have a pitch of 4 pm to 40 pm. In some preferred examples, the outlet layer aerosol forming apertures have a pitch of 8 pm to 20 pm. In some preferred examples, the outlet layer aerosol forming apertures have a pitch of 12 pm to 16 pm

[0042] We also describe a nebulizer comprising a medicinal liquid supply, an aperture plate of any example described herein, and a vibration drive for vibrating the aperture plate to provide aerosol droplets for delivery to a patient’s lungs.

[0043] We also describe a method of manufacturing an aerosolization aperture plate comprising the steps of: providing an inlet layer of material, providing an outlet layer of material, and, in any order: forming an array of reservoir apertures in the inlet layer, forming aerosol-forming apertures in the outlet layer, and bonding the outlet layer and the inlet layer together, and wherein: at least some of the reservoir apertures are each in fluid communication with a plurality of aerosol-forming apertures, and the bonded inlet and outlet layers provide an aperture plate in which the aerosol-forming apertures are in fluid communication with the reservoir apertures.

[0044] In some preferred examples, the inlet layer and the outlet layer are bonded directly together.

[0045] In some preferred examples, the bonding is diffusion bonding.

[0046] In some preferred examples, the aerosol-forming apertures are formed in the outlet layer after bonding to the inlet layer, the inlet layer providing reinforcement during formation of said apertures.

[0047] In some preferred examples, the aerosol-forming apertures are formed by laser drilling. In some preferred examples, the inlet layer and the outlet layer have surface areas which are sufficient for a plurality of aperture plates, and the bonded layers are diced to provide individual aperture plates after the aerosol-forming apertures have been formed.

[0048] In some preferred examples, the inlet layer reservoir apertures are formed before bonding of the layers.

[0049] In some preferred examples, the inlet layer reservoir apertures are formed by laser machining.

[0050] In some preferred examples, at least some of the inlet layer reservoir apertures are formed by etching.

[0051] In some preferred examples, at least some of the inlet layer reservoir apertures are formed by punching or stamping.

[0052] In some preferred examples, the aperture plate is for a nebulizer, for generating aerosol droplets for inhalation.

[0053] In some preferred examples, the aerosol forming apertures are laser drilled in a pattern over at least part of the inlet layer in addition to directly on the outlet layer, the drilling on the inlet layer providing blind holes and the drilling in the outlet layer providing aerosol forming apertures.

[0054] We also describe an aperture plate for aerosolization, the aperture plate comprising: an inlet layer having an array of reservoir holes, and an outlet layer bonded to the inlet layer and having an array of aerosol-forming apertures, in which at least some of the reservoir holes are each in fluid communication with a plurality of aerosol-forming apertures.

[0055] Preferably, the aperture plate is for a nebulizer, for generating aerosol droplets for inhalation.

[0056] In some preferred examples, the layers are directly bonded together. In some preferred examples, the layers are diffusion bonded.

[0057] In various examples: at least one of the layers is of pure metal, optionally platinum or palladium or nickel; and / or at least one of the layers is of a metal alloy, optionally Palladium- Nickel or Hastelloy C276 or Stainless Steel 316L; and / or at least one of the layers is of polymer material, optionally Polyimide; and / or at least one of the layers is of ceramic material, optionally aluminium oxide or aluminium nitride; and / or at least one of the layers is of silicon material, optionally pure silicon or silicon glass; and / or at least one of the layers is of a composite material, optionally Glass Fiber.

[0058] In some preferred examples: both the inlet layer and the outlet layer are of pure metal; or both the inlet layer and the outlet layer are of a metal alloy; or both the inlet layer and the outlet layer are of polymer material; or both the inlet layer and the outlet layer are of ceramic material; or both the inlet layer and the outlet layer are of silicon material; or both the inlet layer and the outlet layer are of composite material.

[0059] In some preferred examples, one or both of the layers are of steel material, such as stainless steel or Hastelloy.

[0060] In some preferred examples, the inlet layer has a thickness in the range of 10 pm to 2000 pm, preferably 20 pm to 200 pm, and more preferably 30 pm to 100 pm.

[0061] In some preferred examples, the reservoir holes in the inlet layer have a diameter in the range of 10 pm to 200 pm, preferably 20 pm to 100 pm and more preferably in the range of 30 pm to 80 pm.

[0062] In some preferred examples, the reservoir hole pitch is in the range of 30 pm to 300 pm, preferably 40 pm to 200 pm, and more preferably 50 pm to 150 pm.

[0063] In some preferred examples, the outlet layer has a thickness in the range of 3 pm to 12 pm, preferably 4 pm to 10 pm.

[0064] In some preferred examples, the outlet holes have a diameter in the range of 0.5 pm to 20 pm, preferably 1 pm to 6 pm, more preferably 1.5 pm to 4.5 pm, and still more preferably 2 pm to 4 pm. In some preferred examples, the outlet holes have a pitch of 4 pm to 40 pm, preferably 8 pm to 20 pm, and still more preferably 12 pm to 16 pm.

[0065] In some preferred examples, the materials of the inlet layer and of the outlet layer are the same.

[0066] We also describe a nebulizer comprising an aperture plate of any example, a liquid supply for delivering liquid to the reservoirs, and a vibration drive for vibrating the aperture plate to provide aerosol droplets for delivery to a patient.

[0067] We also describe a method of manufacturing an aerosol-forming aperture plate, the method comprising the steps of: providing an inlet layer of material, providing an outlet layer of material, and, in any order: forming an array of reservoir holes in the inlet layer, forming aerosol-forming apertures in the outlet layer, and bonding the outlet layer and the inlet layer together, and wherein: at least some of the reservoir holes are each in fluid communication with a plurality of aerosol-forming apertures, and the bonded layers provide an aperture plate in which the aerosol-forming apertures are in fluid communication with the reservoir holes.

[0068] In some preferred examples, the inlet layer and the outlet layer are bonded directly together.

[0069] In some preferred examples, the bonding is diffusion bonding.

[0070] In some preferred examples, the aerosol-forming apertures are formed in the outlet layer after bonding to the inlet layer, the inlet layer providing reinforcement during formation of said apertures.

[0071] In some preferred examples, the aerosol-forming apertures are formed by laser drilling.

[0072] In some preferred examples, the inlet layer and the outlet layer have surface areas which are sufficient for a plurality of aperture plates, and the bonded layers are diced to provide individual aperture plates after the aerosol-forming apertures have been formed. In some preferred examples, the inlet layer holes are formed before bonding of the layers.

[0073] In some preferred examples, the inlet layer reservoir holes are formed by laser drilling.

[0074] In some preferred examples, the inlet reservoir layer holes are formed by etching.

[0075] In some preferred examples, the inlet layer reservoir holes are formed by punching or stamping.

[0076] Detailed Description of the Invention

[0077] The invention will be more clearly understood from the following description of some embodiments thereof, given by way of example only with reference to the accompanying drawings in which:

[0078] Fig. l is a perspective view showing an inlet steel layer over an outlet steel layer, these two layers being for drilling and bonding to provide a nebulizer aperture plate,

[0079] Fig. 2 is a plan view of the inlet layer after it has been perforated by laser drilling to provide an array of reservoirs for the inlet side of the aperture plate, and Fig. 3 is an enlarged view of part of Fig. 2,

[0080] Fig. 4 is a diagrammatic sectional view showing configuration of the inlet layer reservoirs,

[0081] Fig. 5 is a diagrammatic sectional view showing the perforated inlet and the as-yet unperforated outlet layer after bonding,

[0082] Fig. 6(a) is an SEM image with 250x magnification in plan view of the layers before the outlet layer is drilled, Figs. 6(b), (c), and (d) similar views with 500x magnification, lOOOx magnification, and 2,500x magnification respectively,

[0083] Fig. 7 is an image showing a plan view of the inlet layer and the exposed parts of the outlet layer after outlet aerosol-forming apertures have been laser drilled in the outlet layer where it is exposed by the inlet layer cavities / reservoirs,

[0084] Fig. 8(a) is a plan view image of another pair of layers, showing the inlet layer at 45x magnification and the inlet layer having 400 reservoirs, and Fig. 8(b) is an SEM image in plan showing the outlet layer apertures within a single reservoir at lOOOx magnification,

[0085] Figs. 9(a) and (b) are outlet-side plan view images at 250x and l,000x magnifications respectively, showing the arrays of outlet apertures,

[0086] Fig. 10(a) is an inlet-side plan view of part of an example aperture plate, showing part of the outlet layer which is visible through an inlet layer reservoir aperture and the inlet openings of the aerosol-forming apertures are visible, and Fig. 10(b) is an outlet-side plan views showing the exit openings of the aerosol-forming apertures,

[0087] Figs. 11(a), (b), (c), (d), and (e) are a series of images of the inlet side of an aperture plate produced according to the invention with magnifications of 43 x, 500 x, 1 kx, 2.04 kx, and 8.0 kx respectively, and

[0088] Fig. 12 is an image at 2.75 kx magnification showing the outlet side of the aperture plate of Figs. 11(a) to (e), showing the exit openings of the aerosol-forming apertures in the outlet layer.

[0089] Detailed Description of the Embodiments

[0090] The invention provides for aperture plate (“AP”) manufacture in a bi-layer architecture whereby two layers are bonded together to form a composite structure. The bonding may be either directly or via an intermediate layer, preferably directly. Features within each layer may be formed using either additive techniques such as electroforming, micro-moulding or 3D Printing or subtractive techniques such as punching, dry or wet etching, and / or laser drilling. Referring to Fig. 1 two layers are provided at a desired size for manufacture of one or more aperture plates, namely an inlet (or reservoir or reinforcing) layer 100 and an outlet (or delivery) layer 200.

[0091] Advantageously, the inlet layer can be processed individually in a manner which is optimum for providing reservoir or cavity apertures to supply liquid to aerosol forming apertures. Likewise, the outlet layer can be processed in a manner which is optimum for forming the aerosol forming apertures in fluid communication with the reservoirs. Also, the inlet layer can have a thickness which is suited to not only the lengths of the reservoir apertures (or “reservoirs”) but also to provide optimum reinforcement and mechanical properties for high frequency vibration use. This reinforcement may also be used advantageously during manufacture, in which the aerosol-forming apertures are drilled while the outlet layer is supported by the inlet layer and the drilling of the outlet layer is through the exposed surfaces of the outlet layer provided by the inlet layer reservoir apertures.

[0092] The aperture plate is particularly suited to generation of aerosol droplets for pulmonary treatment. The invention also provides a nebulizer comprising an aperture plate of any example, a liquid supply for delivering liquid to the reservoirs, and a vibration drive for vibrating the aperture plate to provide aerosol droplets for delivery to a patient’s lungs. Such a liquid supply and vibration drive are described for example in our published PCT specification WO2021 / 191160.

[0093] Inlet Layer and Forming Reservoir Apertures

[0094] As shown in Figs. 2, 3 and 4, the inlet layer 100 is perforated with an array of apertures which will form reservoirs in the completed aperture plate (“AP”). The inlet apertures may be cylindrical or conical or U-Shaped, may be formed in a rectangular or hexagonal or equilateral triangular or other regular pitch patterns and may have the dimensions and arrangements as set out below. The material of the inlet layer may be a metal, a polymer, a ceramic, or a composite material manufactured for example by micro-injection moulding with for example short glass fibres. However, for most nebulizer applications it is preferred that this layer be of metal, preferably a stainless steel.

[0095] The preferred thickness of the inlet layer will be a function of the material selected, with low density requiring larger thickness than that of higher density materials in order to provide the requisite stiffness for proper operation of the vibrating mesh atomiser. The inlet layer 100 may have a thickness in the range 10 pm to 2000 pm, more preferably in the range 20 pm to 200 pm, more preferably still in the range 30 pm to 100 pm and most preferably in the range 40 pm to 80 pm.

[0096] Diameters, pattern, and pitch are chosen to suit the target nebulization application and for optimum flow of liquid to be aerosolized for applications such as pulmonary drug delivery, with the function of the inlet holes to act as reservoirs supplying underlying aerosol-forming apertures of much smaller diameter. The holes in the inlet layer 100 may have a diameter in the range 10 pm to 200 pm, preferably in the range 20 pm to 100 pm, more preferably still in the range 30 pm to 80 pm and most preferably for some example uses in the range 40 pm to 60 pm, for example 50 pm.

[0097] The hole pitch of the inlet layer 100 may be in the range of 20 pm to 500 pm, more preferably in the range 30 pm to 300 pm more preferably still in the range 40 pm to 200 pm and most preferably in the range 50 gm to 150 gm, for example 100 gm.

[0098] Advantageously, these parameters may be chosen for optimum aerosolization for the desired end use. Where the aperture plate is for use in a nebulizer which is to nebulize any of a range of medicaments including surfactants having a viscosity in a range of up to 15 mPa.s and a surface tension in the range of 15 to 75 mN / m. The reservoirs may preferably have a diameter in the range of 20 to 40 pm and the pitch may be in the range of 50 to 70 pm, for example 30 gm diameter and 60 gm pitch for the reservoirs.

[0099] Inlet Layer Etching to form the Reservoir Apertures

[0100] In one example, the inlet layer 100 is perforated by etching. The process of etching the inlet layer may be described in more detail as follows. A resist is a photoresist when it chemically changes upon exposure to certain wavelengths and if applicable, a subsequent thermal baking step in such a way that the exposed and unexposed resist areas have a different dissolution rate in the developer solution, thus permitting the realisation of a structured photoresist mask. The photoresist material may be applied by spin coating, spray coating or dip coating the substrate. The resin of almost all positive and image reverse resists is a polymerized phenolic resin made of formaldehyde and phenol. The chain length of the resin molecule determines relevant properties of the photoresist. Negative resists cross-link after exposure and a subsequent baking step, while the unexposed part of the resist is dissolved in the developer. Some negative resists are also based on phenolic resin, with a (melamine) cross-linker. Spin-coating is the most common coating technique for resists allowing for very smooth and homogeneous resist films. Spray coating allows the coating of almost arbitrary shaped and textured substrates but in order to attain a smooth and homogeneous resist film thickness as well as a good edge coverage of textures, an optimized resist composition with different solvents with low and high boiling points is required. Dip coating techniques are used for large, rectangular shaped substrates and the demand for a minimum resist consumption per coated area. For a homogeneous resist film thickness over the entire substrate, a certain solvent composition in the resist is required. Masking is performed using standard photolithographic methods by application, exposure and developing of the photoresist material onto the surface of the material which is required to be etched.

[0101] Wet etching is a material removal process that uses liquid chemicals or etchants to remove materials from a wafer. The specific patterns are defined by the photoresist masks on the wafer. Materials that are not protected by this mask are etched away by liquid chemicals. Dry etching is often an anisotropic process in which the momentum of ion species accelerating towards the substrate in combination with a masking process is used to physically remove and etch the target materials. Dry etching requires an elevated softening point of the resist as well as steep sidewalls.

[0102] In one example, spin coating of AZ40XT-11D™ (Merck Performance Materials) Chemically Amplified Photoresist is applied to a 50um thick sheet of 304 Stainless Steel using dynamic spincoat dispense at 30 rpm to provide a 40 pm thick film. This was followed by a soft bake at 125 °C with proximity for 120 s at 1.27 mm, 120 s at 0.63 mm and 180 s contact. Exposure was carried out using a Suss MA-200™ aligner with a 20 pm proximity gap and 900 mJ / cm2nominal exposure dose. Post expose bake was completed at 105 °C with proximity for 10 at 1.3 mm, 10 s at 0.6 mm and 80 s contact. This was followed by development using AZ 300MIF™ (Merck Performance Materials™), with 3 x 40 second puddles. Spray etching of the stainless steel was carried out using Ferric Chloride (FeC13) at a specific gravity of 1.292 with IMol Hydrochloric Acid (HC1) at a temperature of 50 °C for 5 minutes to create fully etched through holes. In one example, the etched holes have a diameter of 100 pm and a pitch in both orthogonal directions of 150 pm.

[0103] Inlet Layer Electroforming to form the Reservoir Apertures

[0104] In another example, the inlet layer may be created using electroforming, an example process being described in US4, 844,778 (Stork Veco B.V.).

[0105] Inlet Layer Mechanical Operations to form the Reservoir Apertures

[0106] In another example, the inlet layer is processed by punching or stamping. Stamping is a fabrication process that presses a work piece, such as a metal strip, between a die set assembly into a predetermined shape or pattern. Stamping presses and stamping dies are tools used in the stamping process. The die set assembly can perform various operations on the work piece, such as cutting and forming operations like punching, drawing, bending, flanging and hemming. Stamping processes have been deployed in manufacturing processes for mass-producing parts at low cost. Conventional stamping processes have not been effective in producing parts with acceptable tolerances for high precision components as are typically used in the manufacture of aperture plates for vibrating mesh nebulisers. It is therefore desirable to have a manufacturing technology capable of producing parts for precision applications with tolerances within 1,000 nanometres and capable of running at very high speeds.

[0107] Stamping systems for manufacturing high tolerance parts are described in for example EPl 536931 (Nanoprecision products Inc.). The system includes one or a progression of stamping stations for supporting a punch or die. The stamping stations include a structure for guiding the punch in substantial alignment with the die with tight tolerances. The system includes a press for providing the stamping stations with the necessary force to perform the particular stamping operation. In one aspect of the present invention, the system is designed to minimize the number of moving components involved in the support structure in guiding the punch to the die. In another aspect, the system includes a locating sub-plate having indexing features for precisely aligning the progression of stamping stations relative to each other. The locating sub- plate and its indexing features have exacting tolerances and submicron surface finishes. In a further aspect, the system includes an interface system for coupling the force of the press with the punch but structurally decoupling the press from the punch. The interface system also allows isolation of each stamping station so that operation at one station does not affect operation at another station. A punching or stamping process is particularly efficient for high volume manufacture (greater than approximately 100000 units), whereas additive techniques may be used advantageously for smaller batches.

[0108] In various examples the inlet layer may be formed by hot embossing, moulding, inkjet, or 3D Printing, Lost Wax or LIGA (Lithography, Electroforming and Moulding) Processing, Microinjection moulding or UV Nanoimprint Lithography. These processes have the potential of creating complex and intricate geometries down to the micron scale. The process is not limited to a single step. If required, multiple processes can be used in conjunction to achieve the desired result.

[0109] Hot embossing is a process which relies on increasing the temperature of a polymer sheet above its melting range followed by pressing a heated mould into the polymer, generating pressure to fill the surface structures. In hot embossing, a mould is attached to one clamp, and the polymer material or substrate is attached to another clamp, both clamps are heated, one clamp is stationary while the other lowers slowly and gradually as the polymer slowly deforms around the mould. When it is lowered, the polymer is softened and forms into the shape of the mould. The process takes between 5 - 30 mins to complete. The applications of hot embossing can be found in optical devices such as compact discs, lenses, mirrors, optical benches, wave guides and switches (Omar 2013,

[0015] ) and (Becker & Heim, 1999, [3]). Common materials used in hot embossing are Polycarbonate (PC), Cyclic Olefin Copolymers (COC) and Polymethylmethacrylate (PMMA). Micro injection is very similar to standard injection moulding, but on a micro-scale. Similar to standard injection moulding, polymer granules are fed into the hopper, are pushed along the barrel where they are softened and molten, and then injected into a mould under pressure where it solidifies. (Surace, et al., 2012,

[0019] ) and (Omar, 2013,

[0015] ).

[0110] 3D Printing of the Inlet Layer to form the Reservoir Apertures

[0111] Manufacture of the inlet layer may alternatively be by way of 3D printing. There are many 3D printing techniques, all with varying production speeds, feedstock material choices and resolution capabilities. Basic FDM (Fused Deposition Modelling) 3D printing adds layers on top of layers through a hot nozzle (called the extruder) of a set diameter to produce the 3D object (O'Neal, 2019). Advanced printers using lasers on photosensitive materials, such as Multiphoton Lithography can have high resolution (-250 nm) and can produce parts down to the micrometre scale. (Prabhakaran, 2019).

[0112] Another manufacturing approach is Digital Light Processing (DLP) and Stereo Lithography (SLA), both methods used in 3D printing with resin baths, and both use UV light on photosensitive resin to harden it. In both printing methods, a platform is moved vertically as layer by layer is being solidified by the laser / projector. A DLP printer can print faster compared to SLA, therefore it has the ability to solidify an entire plane at a time, compared to SLA which is essentially drawing the objects layer by layer with a singular laser. The accuracy and resolution can also vary between the two processes. In DLP printing, square pixels are applied in a combination to solidify the resin which causes the 3D object to have steps around the edges. However, this process is being refined and anti-aliasing techniques are being applied with a specific kind of DLP printing called CDLM DLP printing. The anti-aliasing function essentially smoothens the edges of the subject removing the steps. Any photopolymer can be used in either of these two processes, therefore theoretically if a photo-initiator is introduced into a polymer, it can be used as the resin for SLA / DLP printing (Waheed, et al., 2016).

[0113] Nanoimprint Lithography (NIL) can create sub-micron features on a polymer surface such as a diaphragm. It creates a pattern via deformation onto a resist material using a mould. There are many types of lithography, but two fundamental types are Thermal Nanoimprint Lithography (T- NIL) and UV Nanoimprint Lithography (UV-NIL) with both being capable of creating features as small as 10 nm. The main differences between T-NIL and hot embossing are that hot embossing is slower and can work on larger mould structures. NIL applications mainly cover nanoelectronics, nano-optoelectronics, nanophotonic, nano-biology, optical components, etc. (Omar, 2013,

[0015] ).

[0114] Table 1 is a summary comparison of the process parameters for some of the techniques described above. Table 1.

[0115] The inventors believe that of the examples in this table, for large volume aperture plate manufacture, injection moulding is preferable to UV imprinting, which is n turn preferable to hot embossing.

[0116] Inlet Layer Laser Machining to form the Reservoir Apertures

[0117] In one example, the material of the inlet layer 100 is rolled shim stock stainless steel 316 L, it has a thickness of 50 pm, and it is perforated by laser drilling using a laser drilling technique such as described in US7, 316,067 (The Technology Partnership). A benefit of laser machining is that it can work with a wide range of materials, including alloys which are very corrosion resistant, such as Hastelloy, and which are therefore not very suitable for etching.

[0118] To achieve the desired reservoir hole sizes in the inlet layer laser machining may be performed, one reason being that it can be effective for working with an inlet layer material which is highly corrosion resistant, such as Hastelloy.

[0119] In one approach there is percussion drilling to provide tapered, funnel-shaped, reservoir apertures with exit diameters of about 27 pm and an entrance diameter of about 85 pm. Percussion drilling means that there are multiple pulses of a large laser spot with a defined repetition rate at the same position. Percussion drilling is known for its high efficiency, as it does not require relative movement between the laser beam and the workpiece. However, exceeding optimal pulse counts may lead to deteriorated edge quality due to increased striations and irregularities.

[0120] In another approach there is trepanning with a drilling time of 2.5 - 4.5 min / AP — lO h - 18 h / wafer sheet. Trepanning means that there is a small laser spot scanned along a circle contour for multiple iterations. This technique allows for precise control over hole geometry and is particularly beneficial when high dimensional accuracy and edge quality are required. Shorter pulse durations result in reduced thermal effects and improved hole circularity. Trepanning is generally slower than percussion drilling.

[0121] A further approach is preferred, high ablation rate drilling. Reservoir apertures were achieved with a 50 pm exit diameter and a pitch of 100 pm, and in other examples a 70 pm exit diameter and a pitch of 120 pm. High-rate ablation utilizes ultrafast lasers with high repetition rates to rapidly remove material, enabling the creation of holes with minimal thermal impact. This method is advantageous for applications requiring high precision and minimal heat-affected zones. However, achieving optimal results with high-rate ablation requires careful control of laser parameters, such as fluence, pulse duration, and repetition rate, to balance material removal rate and hole quality. Inclusion of a quarter wave plate to generate circular polarization will result in good roundness at the exit side of the holes.

[0122] Laser machining of the inlet layer (50 pm thick) to create holes ranging from 30 pm to 100 pm in diameter can be effectively achieved using any of these three laser drilling techniques. Each method offers distinct advantages and considerations, depending on the specific requirements of the aperture plate. Selecting the appropriate laser drilling technique for the inlet layer depends on the specific requirements of hole size, quality, and production speed. Percussion drilling offers high efficiency for rapid hole creation but may compromise on edge quality. Trepanning provides good precision and edge quality, but is slower. High-rate ablation offers a balance between speed and quality, especially when minimal thermal impact is desired. This is preferred for this application of forming reservoir apertures for manufacture of nebulizer aperture plates, because of speed, ability to achieve a nearly straight cylindrical shape and hence higher aperture density.

[0123] Outlet Layer

[0124] As shown in Fig. 5 the outlet layer 200 has a thickness much smaller than the inlet layer 100. For use in vibrating mesh nebulisers, the material for the outlet layer 200 would need to be strong, durable, biocompatible, corrosion resistant, and capable of being formed into very thin sheets and bonded to the inlet layer using any of the techniques described.

[0125] The outlet layer may have a thickness in the range 1 pm to 20 pm, more preferably in the range 3 pm to 12 pm, more preferably still in the range 4 pm toOpm and most preferably in the range 5 pm to 7 pm, for example 6 pm. In one preferred example the thickness is 7.5 pm.

[0126] In some examples, the material of the outlet layer is a pure metal or metal alloy such as 316L or 304 Stainless Steel or other highly corrosion resistant metal alloys such as Hastelloy C276, SS Nitronic 60™, BioDur™, ASTMF1586 or the like. It is advantageous that the outlet layer be of a metal, as that provides excellent resistance to cracking in the high frequency vibration operation of nebulizers. Also, metal alloys can be very corrosion resistant. Moreover, where both layers are of metal, and especially an alloy such as stainless steel, diffusion bonding is particularly preferred for bonding of the layers. This avoids need for a third material in-between, and achieves excellent structural integrity and resistance to cracking and de-lamination. The result is that the end product aperture plate is effectively integral.

[0127] In another example, although not preferred, the material of the outlet layer may be silicon or epoxy or a durable polymer material such as, Acrylic, Polyimide, Ultra-High Molecular Weight Polyethylene (UHMWPE), Polyetheretherketone (PEEK), Polytetrafluoroethylene (PTFE_ or other Fluoropolymers, Silicon, Bioglass, Alumina, Zirconia, Vitreous Carbonor or the like.

[0128] The material of the outlet layer may be of the same or of a different material as is used in the inlet layer. Diffusion bonding allows the layers to be of different materials, and a major consideration is that a different material may be preferred because the outlet layer is much thinner than the inlet layer. For example, if the outlet layer has a thickness at the lower end of the above ranges, such as say 4 pm, such material may not be readily available as a 316L stainless but it available as a 304 stainless steel (which is less corrosion resistant then 316L).

[0129] In one example, the material of the outlet layer is shim stock 304 grade stainless steel with a thickness of 8 pm produced by a standard cold rolling process. In another example, the material of the outlet layer is a corrosion resistant Hastelloy C276 nickel alloy with thickness of 10pm.

[0130] Bonding of the Inlet and Outlet Layers Together

[0131] The inlet and outlet layers are bonded together, and this is preferably done with a bonding technique which does not include a third material and achieves molecular-level bonding, a preferred example being diffusion bonding. This may be performed alternatively using an adhesive or adhesive film or laminating, or induction metal polymer bonding. Alternatively, the layers may be fused together using suitable intermetallic metallurgical joining techniques such as Laser Welding, Resistance Spot Welding, Friction Stir Welding, Friction Stir Spot Welding, Electron Beam Welding, Transient Liquid Phase or Diffusion Bonding (solid-state or liquid phase).

[0132] Diffusion Bonding

[0133] The solid-state diffusion bonding process (Akselsen, 1992, [1]), (Mahoney, 1993,

[0014] ), (Kazakov, 2013,

[0012] ), (AlHazaa, 2020, [2]), (Cooke, 2020, [5]), involves heating of the mating surfaces to a suitable elevated temperature, typically between 60% and 80% of the melting point temperature of the lowest melting point base metal or interlayer. The process contains several steps. The first step involves contact in which surface asperities are deformed as the surfaces to be joined under the effects of heat and static pressure. The second stage is heating, followed by holding the samples at the bonding temperature to facilitate the formation of the joint. During the heating and holding stage of the bonding process, inter-diffusion takes place between the base metals and or base metal and interlayer. Parameters of importance in solid-state bonding are bonding time, contact pressure, bonding temperature, surface roughness, and interlayer composition. The effect of surface treatment on bond strength varies with the quality of the surface treatments, which can range from an electropolished finish to turning in a lathe or wire brushing. The results indicate that as the surface roughness increases, the bond strength decreases, which implies that during solid state bonding, surface roughness is of considerable significance. Higher pressures are typically required to achieve plastic deformation and oxide breakup at the interface and creating an intimate contact between the materials.

[0134] The invention includes bonding techniques such as use of adhesives or welding. However, use of such techniques involves the introduction of a tertiary material which can be susceptible to degradation upon exposure to the harsh environments typically used for general purpose medical vibrating mesh nebulisers. For example, adhesives are subject to chemical degradation in highly acidic and alkaline environments or at elevated transport and storage temperature and humidity conditions. Welding with a tertiary dissimilar filler material causes inter-atomic diffusion of the filler material into the individual inlet and outlet layers and causes embrittlement of the co-alloys thus formed in these regions. This presents issues with fatigue life for extended use periods and can result in inter-later delamination with resultant mesh cracks and fractures causing catastrophic failure of the device and potential for materials thus liberated to enter the patient airways. In contrast, diffusion bonding creates high-strength bonds, comparable to the base metal's strength, preserves the microstructure at the joint, minimises distortion and residual stress and creates no localized thermal gradient this reducing potential for warping or stress. It is suitable for joining complex shapes and dissimilar materials Diffusion bonding uses no tertiary filler material and results in a cohesive bond between inlet and outlet layers though atomic-level diffusion of the base metals used for the individual layers. In this way, the end product aperture plate can operate reliably, with low risk of bond degradation even in the harsh environmental and operating conditions traditionally experienced by medical grade nebulisers. As a result, the end product aperture plate has the structural integrity of a plate which was always integral, and the manufacturing method has the benefit of being able to form the reservoir and aerosol-forming apertures separately. Also, drilling of the latter apertures has the benefit of being performed with the inlet layer providing reinforcement.

[0135] The outlet layer may be perforated prior to or after bonding with the inlet layer. Advantageously the inlet layer provides very significant reinforcement during manufacturing if the outlet layer is perforated with the aerosol-forming apertures after bonding to the inlet layer. Such perforation is through the inlet layer apertures which expose the inlet-side surface of the outlet layer. The outlet layer perforation is preferably performed by laser drilling. Laser drilling of the aerosol-forming apertures is particularly preferred because it can be accurately performed through the inlet layer apertures.

[0136] The driving force of the bonding process is diffusion, as described by Fick’s laws. Bonding pressures ranging from 1 to 10 MPa, bonding temperatures ranging from 600 to 1000 °C and bonding times ranging from 30 to 120 mins are typical for the diffusion bonding process. In one example, a 50 pm thick chemically etched inlet layer made of 316L Stainless Steel was diffusion bonded to a 12 pm thick cold rolled 304 Stainless Steel sheet using solid state diffusion bonding. Figs. 6(a) to (d) are SEM images of the above-mentioned example at increasing magnification showing top plan views of the inlet and outlet layers after bonding by diffusion bonding.

[0137] Pre-Bonding Preparation

[0138] Surface Cleaning and Conditioning

[0139] Effective surface preparation helps successful diffusion bonding, especially with stainless steel alloys such as SS316, which naturally form passive oxide layers that can impede atomic diffusion at the bonding interface. Removal of Native Oxide Layers

[0140] SS316 forms a stable chromium oxide (C CE) layer that inhibits diffusion bonding. To remove this layer the following steps may be performed:

[0141] Mechanical Polishing: Achieve a surface roughness of less than 0.1 pm Ra through fine polishing techniques. This reduces surface asperities and enhances contact at the bonding interface.

[0142] Chemical Cleaning: Employ acid treatments such as dilute nitric acid (HNOs) or hydrochloric acid (HC1) to dissolve the oxide layer. Care must be taken to control concentration and exposure time to prevent pitting or intergranular corrosion.

[0143] Plasma Cleaning: Utilize low-pressure plasma to remove organic contaminants and thin oxide layers without introducing additional chemicals. This method also increases surface energy, promoting better bonding.

[0144] Degreasing

[0145] Prior to oxide removal, the surfaces should be degreased to eliminate organic contaminants: Solvent Cleaning: Use solvents like acetone or ethanol to remove oils and greases. Ensure that the solvents are of high purity to avoid leaving residues.

[0146] Ultrasonic Cleaning: Submerge parts in an ultrasonic bath with a suitable cleaning solution to dislodge particulates and contaminants from intricate features, such as laser-drilled holes.

[0147] Drying and Handling

[0148] After cleaning:

[0149] Drying: Use filtered, dry nitrogen or clean air to dry the components, minimizing the risk of recontamination.

[0150] Cleanroom Assembly: Assemble the components in a cleanroom environment to prevent particulate or organic contamination. Use powder-free gloves and handle parts with tools to avoid direct contact.

[0151] Flatness and Fixturing

[0152] Maintaining flatness and proper fixturing is important, especially because the outlet layer is a thin foil for example with a thickness of only 7.5 pm such as SS316 sheets.

[0153] Ensuring Planarity

[0154] Surface Flatness: Achieve a flatness tolerance within 5 pm across the bonding surfaces to ensure uniform contact. Polishing: Utilize precision polishing techniques to attain the required flatness, which is critical for minimizing voids and ensuring consistent diffusion across the interface.

[0155] Fixturing Techniques

[0156] Bonding Jigs: Employ precision-engineered bonding jigs or fixtures that apply uniform pressure across the entire bonding area. Materials like graphite are preferred due to their thermal stability and minimal reaction with stainless steel.

[0157] Diffusion Barriers or Shim Layers: Introduce compliant layers or shims to accommodate minor surface irregularities and distribute pressure evenly, preventing localized deformation or damage to the thin foils.

[0158] Alignment

[0159] Registration Features: Incorporate alignment holes or fiducial marks into the laser-drilled sheets to facilitate precise alignment during assembly. This ensures that features such as microchannels or vias (small laser drilled holes) are properly registered post-bonding.

[0160] Transient Liquid Phase (TLP) Diffusion Bonding

[0161] An interfacial area between the layers may be used but should be free of voids or other foreign matter and the reservoir areas should be free of melt / ingress of material used within the interfacial layer. Transient liquid phase (TLP) bonding may also be used to bond metallic inlet and outlet layers in a form of diffusion bonding , although it involves bringing the materials above melting point. During TLP bonding, a liquid form at the interface wets and spreads between the surfaces by capillary action. Bonding parameters such as temperature, time, interlayer composition, and thickness have a considerable impact on the quality of the weld / bond. However, unlike solid-state diffusion bonding, high pressures are not required to achieve contact between the surfaces. The type of interlayer selected determines the temperature at which liquid forms at the interface. In some cases, interdiffusion between the interlayer and the base metal leads to the formation of eutectic composition, which melts at the bonding temperature. Alternatively, an interlayer having a eutectic or peritectic composition would melt at the bonding temperature. TLP bonding contains four stages: heating melting and widening, isothermal solidifications, and homogenization for the bond region. The driving force for the TLP process is the diffusion coefficient, which varies from liquid-phase diffusion during stage one, to solid-state diffusion during stage two of the bonding process. When the interlayer melts, the liquid wets the base metal surface and is then drawn into the joint by capillary action.

[0162] One of the key advantages of TLP bonding is the ability to use lower bonding temperatures as these are determined by the melting point of the material selected for the interlayer. Bonding may be achieved below 150°C using a Cu / Sn / In-Sn / Cu assembly, leveraging the low eutectic point of In-Sn while Au / In TLP joints may be fabricated at 180°C. If a tin-based interlayer is used, the bonding temperature might be around 280°C while bonding temperatures between 400°C and 700°C are possible with a Ni-Sn interlayer. This lower bonding temperature provide some versatility in the selection of, and may in some cases offer advantage in terms of impact on the microstructure, of the parent materials used for the individual layers to be bonded

[0163] Laser Drilling of the Aerosol-Forming Apertures

[0164] After bonding of the layers, laser is performed through the reservoirs 101 to drill small aerosolforming apertures 201 in the outlet layer, in this case 22 outlet apertures 201 per reservoir 101, see Fig. 7.

[0165] Laser drilling is performed according to the laser drilling processes described in US7, 316,067 (The Technology Partnership). Laser drilled holes in the outlet layer may range from 0.5 pm to 20 pm in diameter, preferred in the range 1 pm to 6 pm, still more preferred on the outlet end in the range of 1.5 pm to 4.5 pm, most preferred in the range 2.0 pm to 4.0 pm, for example 3.0 pm. The outlet layer holes may be at a pitch of 4 pm to 40 pm, preferred in the range of 8 pm to 20 pm and most preferred in the range of 12 pm to 16 pm, for example 14 pm in a rectangular or hexagonal or other regular pitch pattern.

[0166] It is very advantageous that the inlet layer not only provides the body for the reservoirs in the endproduct aperture plate, but during manufacture it also provides a strong reinforcement for support of the outlet layer during drilling of the aerosol-forming apertures. It is preferred that the ratio of the thickness of the inlet layer to that of the outlet layer is in the range of 2: 1 to 25:1, preferably 5: 1 to 25: 1.

[0167] Figs. 8(a) and (b) show an example of a bonded and laser drilled aperture plate, in which an inlet layer 1100 of a finalised aperture plate has 400 apertures 1101 with diameters in the region of 100 pm. In the outlet layer 1200 there are about 30 aerosol-forming apertures 1201 within each reservoir 1101, providing a total of 12,000 aerosol forming apertures per aperture plate. The total possible number of aerosol-forming apertures per aperture plate is determined by the diameter and pitch of reservoirs in the inlet layer coupled with the diameter and pitch of the apertures in the outlet layer.

[0168] Figs. 9(a) and (b) shows the outlet side, on which there is an array of groups of outlet apertures 1201 each group being at the bottom of a single reservoir 1101. The outlet layer apertures may be cylindrical or conical or U-Shaped. In this example the outlet layer apertures are cylindrical in shape and have a diameter at the outlet side of the outlet layer ranging from 1.86 pm to 4.22 pm with an average diameter of all apertures of 3.50 pm.

[0169] Fig. 10(a) is an inlet-side plan view of part of an example aperture plate, showing part of the outlet layer 2200 which is visible through an inlet layer reservoir aperture and the inlet openings 2202 of the aerosol-forming apertures 2201 are visible. Fig. 10(b) is an outlet-side plan views showing the exit openings 2203 of the aerosol-forming apertures. In various measurements here the aperture inlet openings shown in Fig. 10(a) are about 9 pm and the pitch is about 20 pm. As shown in Fig. 10(b) on the outlet side there is of course the same pitch but an opening diameter of about 3.3 pm on average.

[0170] Figs. 11(a), (b), (c), (d), and (e) are a series of images of the inlet side of an aperture plate produced according to the invention with magnifications of 43 x, 500 x, 1 kx, 2.04 kx, and 8.0kx respectively. The aperture plate has an inlet layer of 316L stainless steel of thickness of 51 pm, and an outlet layer of 316 stainless steel of thickness of 7.5 pm. Fig. 11(a) shows the full aperture plate 3000, the inlet layer being 3100 and the reservoirs being 3101. Figs. 11(b) onwards show the outlet layer in more detail, through the reservoirs 3101, within which the aerosol -forming apertures 3201 are visible. In this case the laser drilling of the aerosol-forming apertures is performed in a blanket manner across all of the area of the inlet layer to provide the apertures 3201 where only the outlet layer is present and blind holes 3201(a) in the inlet layer. The latter perform no useful function in aerosolization; however, it is simpler to drill in a “blanket” manner such as this as it avoids need to perform laser positioning to drill only through the reservoirs. While the blind holes 3201(a) in the inlet layer perform no aerosolization function, they do not do any harm and indeed they contribute to flexibility of the aperture plate in addition to allowing simpler and faster manufacturing. In these images, measurements have been performed on some of the reservoir apertures, in one case one reservoir aperture inlet side opening having a diameter of 74.04 pm, and the centre-to centre distances or pitches LI, L2, and L3 are all in the region of 118 to 119 pm. In Fig. 11(e) sample aerosol forming aperture diameters Cl, C2, and C3 are all in the region of 5.1 to 5.7 pm and the pitch values LI, L2, and L3 are in the region of 9.6 pm to 9.8 pm.

[0171] Fig. 12 is an image at 2.75 kx magnification showing the outlet side of the aperture plate of Figs. 11(a) to (e), showing the exit openings of the aerosol-forming apertures 3201 in the outlet layer. These are in the region of 1.8 pm to 2.3 pm. Tests were carried out with the aperture plate of Figs. 11 and 12. In one test the liquid was 0.058% saline, and the flow rate achieved was 1.73 mL / min and the VMD was 5.4 pm. In another test the liquid was a medicament with a surface tension of 47mN / m and a viscosity of 1.2-1.5mPa s and the average flow rate was 0.46 mL / min.

[0172] After the layers have been bonded and the outlet layer drilled the resulting wafer sheet may be punched to provide individual aperture plates of say 5 mm diameter. Also, the aperture plates may be pressed to form a dome shape with a flanged rim. This rim is suitable for bonding to a washershaped support.

[0173] The following are some aspects of laser drilling of the aerosol-forming apertures in the outlet layer.

[0174] Minimal Thermal Impact:

[0175] Ultrafast pulsed lasers (femtosecond or picosecond) minimize heat-affected zones, preventing thermal damage to the delicate outlet layer, preserving bond integrity.

[0176] Versatility in Materials:

[0177] Laser drilling can process diverse materials for the outlet layer (metals, polymers, ceramics), making it adaptable for different nebulizer designs.

[0178] Little Mechanical Stress:

[0179] As a non-contact process, it avoids mechanical deformation of the outlet layer, preserving the structural integrity of the diffusion bond.

[0180] Complex Geometries and Patterns:

[0181] Custom hole patterns can be created in the outlet layer (e.g., varying diameters, shapes) to optimize droplet formation.

[0182] High Aspect Ratio Capabilities:

[0183] Even at small thicknesses such as 7.5pm, laser drilling maintains precise, high-aspect-ratio holes, essential for droplet control.

[0184] Speed and Scalability:

[0185] The process is scalable, allowing rapid and consistent production of high-quality nebulizer meshes. Optimal Laser Parameters for Fine Drilling in Diffusion-Bonded Setup Laser Type: Femtosecond or Picosecond Laser

[0186] Preferred Option: Femtosecond laser (10-300 fs) for minimal heat-affected zone.

[0187] Alternative: Picosecond laser (1-10 ps) for balanced precision.

[0188] Wavelength Selection:

[0189] Ultraviolet (UV, 355 nm): Ideal for minimal heat-affected zone in Layer B.

[0190] Green (532 nm): Suitable for a range of Layer B materials.

[0191] Power and Energy Control:

[0192] Pulse Energy: Low (sub-microjoule) to prevent thermal damage.

[0193] Repetition Rate: 100 kHz - 1 MHz for balance between speed and control.

[0194] Focus Control: High NA lens for precise targeting of the outlet layer.

[0195] Beam Control:

[0196] Spot Size: Adjustable (1-10 pm) for fine hole diameter.

[0197] Beam Shaping: For consistent geometry of each hole in the outlet layer.

[0198] Laser drilling, especially fine drilling using femtosecond or picosecond lasers, offers a precise, scalable solution for creating consistent, high-quality holes in the second layer of a diffusion- bonded mesh. This approach ensures optimized droplet generation in vibrating mesh nebulizers.

[0199] The invention provides the benefit of providing two separate and distinct layers, one optimised for aperture plate reinforcement and provision of reservoirs, and the other being optimized for aerosol formation. The layers are bonded together to create a fused bi-layer structure, the architecture of which is compatible with further processing to generate aerosol forming apertures. Processing techniques and materials employed in this invention are of low cost and are easily scalable to high volumes. The invention provides a scalable, high yield, low-cost process for generating high performing aperture plates for use in vibrating mesh nebulisers. The raw material used for the mesh may be low cost, readily available to extremely tight tolerances and compatible with all processes under consideration. This invention would find commercial application with conventional drugs for inhalation and for specific drugs for targeted applications which are challenging to deliver with the standard single layer electroformed geometry or with geometries feasible to make when utilising singular processes such as electroforming only or laser micromachining and drilling only. The invention provides an adaptable / versatile aperture geometry to enable nebulisation of different drugs. Components of embodiments can be employed in other embodiments in a manner as would be understood by a person of ordinary skill in the art. The invention is not limited to the embodiments described but may be varied in construction and detail.

Claims

Claims1. An aperture plate for aerosolization, the aperture plate comprising: an inlet layer (100) having an array of reservoir apertures (101), and an outlet layer (200) bonded to the inlet layer and having an array of aerosolforming apertures, in which at least some of the reservoir apertures are each in fluid communication with a plurality of aerosol-forming apertures (201).

2. An aperture plate as claimed in claim 1, wherein the aperture plate is a nebulizer aperture plate, for generating aerosol droplets for inhalation.

3. An aperture plate as claimed in claim 1 or claim 2, wherein the layers are directly bonded together.

4. An aperture plate as claimed in claim 3, wherein the layers are diffusion bonded together.

5. An aperture plate as claimed in any preceding claim, wherein at least one of the layers is of a metal alloy, optionally Palladium- Nickel or Hastelloy C276 or Stainless Steel 316L.

6. An aperture plate as claimed in claim 5, wherein both the inlet layer and the outlet layer are of a metal alloy.

7. An aperture plate as claimed in any preceding claim, wherein one or both of the layers are of steel material, optionally stainless steel such as Hastelloy.

8. An aperture plate as claimed in any preceding claim, wherein the inlet layer and the outlet layer are of a stainless steel material, and they are diffusion bonded together.

9. An aperture plate as claimed in any preceding claim, wherein the inlet layer has a thickness in the range of 10 pm to 2000 pm.

10. An aperture plate as claimed in any preceding claim, wherein the inlet layer has a thickness in the range of 20 pm to 200 pm.

11. An aperture plate as claimed in any preceding claim, wherein the inlet layer has a thickness in the range of 30 pm to 100 pm.

12. An aperture plate as claimed in any preceding claim, wherein the reservoir apertures in the inlet layer have a diameter in the range of 10 pm to 200 pm.

13. An aperture plate as claimed in any preceding claim, wherein the reservoir apertures in the inlet layer have a diameter in the range of 20 pm to 100 pm.

14. An aperture plate as claimed in any preceding claim, wherein the reservoir apertures in the inlet layer have a diameter in the range of 30 pm to 80 pm.

15. An aperture plate as claimed in any preceding claim, wherein the reservoir aperture pitch is in the range of 30 pm to 300 pm.

16. An aperture plate as claimed in any preceding claim, wherein the reservoir aperture pitch is in the range of 40 pm to 200 pm.

17. An aperture plate as claimed in any preceding claim, wherein the reservoir aperture pitch is in the range of 50 pm to 150 pm.

18. An aperture plate as claimed in any preceding claim, wherein the outlet layer has a thickness in the range of 3 pm to 12 pm.

19. An aperture plate as claimed in any preceding claim, wherein the outlet layer has a thickness in the range of 4 pm to 10 pm20. An aperture plate as claimed in any preceding claim, wherein the outlet layer aerosol forming apertures have a diameter in the range of 0.5 pm to 20 pm.

21. An aperture plate as claimed in any preceding claim, wherein the outlet layer aerosol forming apertures have a diameter in the range of 1 pm to 6 pm.

22. An aperture plate as claimed in any preceding claim, wherein the outlet layer aerosol forming apertures have a diameter on the outlet end in the range of 1.5 pm to 4.5 pm, and optionally in the range of 2 pm to 4 pm.

23. An aperture plate as claimed in any preceding claim, wherein the ratio of the thickness of the inlet layer to that of the outlet layer is in the range of 2: 1 to 25: 1, optionally in the range of 5: 1 to 25: 1.An aperture plate as claimed in any preceding claim, wherein the outlet layer aerosol forming apertures have a pitch of 4 pm to 40 pm.

25. An aperture plate as claimed in any preceding claim, wherein the outlet layer aerosol forming apertures have a pitch of 8 pm to 20 pm.

26. An aperture plate as claimed in any preceding claim, wherein the outlet layer aerosol forming apertures have a pitch of 12 pm to 16 pm27. A nebulizer comprising a medicinal liquid supply, an aperture plate of any of claims 1 to 26, and a vibration drive for vibrating the aperture plate to provide aerosol droplets for delivery to a patient’s lungs.

28. A method of manufacturing an aerosolization aperture plate comprising the steps of: providing an inlet layer (100) of material, providing an outlet layer (200) of material, and, in any order: forming an array of reservoir apertures (101) in the inlet layer, forming aerosol-forming apertures (201) in the outlet layer, and bonding the outlet layer and the inlet layer together, and wherein: at least some of the reservoir apertures are each in fluid communication with a plurality of aerosol-forming apertures, and the bonded inlet and outlet layers provide an aperture plate in which the aerosol-forming apertures are in fluid communication with the reservoir apertures.

29. A method as claimed in claim 28, wherein the inlet layer and the outlet layer are bonded directly together.

30. A method as claimed in claim 28 or claim 29, wherein the bonding is diffusion bonding.

31. A method as claimed in any of claims 28 to 30, wherein the aerosol-forming apertures (201) are formed in the outlet layer after bonding to the inlet layer, the inlet layer providing reinforcement during formation of said apertures.

32. A method as claimed in any of claims 28 to 31, wherein the aerosol-forming apertures are formed by laser drilling.

33. A method as claimed in any of claims 28 to 32, wherein the inlet layer and the outlet layer have surface areas which are sufficient for a plurality of aperture plates, and the bonded layers are diced to provide individual aperture plates after the aerosol-forming apertures have been formed.

34. A method as claimed in any of claims 28 to 33, wherein the inlet layer reservoir apertures are formed before bonding of the layers.

35. A method as claimed in any of claims 28 to 34, wherein the inlet layer reservoir apertures are formed by laser machining.

36. A method as claimed in any of claims 28 to 35, wherein at least some of the inlet layer reservoir apertures are formed by etching.

37. A method as claimed in any of claims 28 to 36, wherein at least some of the inlet layer reservoir apertures are formed by punching or stamping.

38. A method as claimed in any of claims 28 to 37, wherein the aperture plate is for a nebulizer, for generating aerosol droplets for inhalation.

39. A method as claimed in any of claims 28 to 38, wherein the aerosol forming apertures are laser drilled in a pattern over at least part of the inlet layer in addition to directly on theoutlet layer, the drilling on the inlet layer providing blind holes (3201(a)) and the drilling in the outlet layer providing the aerosol forming apertures (3201).

Images