Multi-surface acoustic wave nebulizer

Abstract

To provide a practical and commercially realizable nebulizer that can be used reliably and easily by end users.SOLUTION: A nebulizer for nebulizing liquid droplets includes: a housing; at least one piezoelectric substrate 2 accommodated within the housing and having a transducer surface 2a upon which at least one electroacoustic transducer for generating acoustic wave energy within the substrate is located, and an opposing non-transducer surface 2b; and a liquid supply system for supplying a liquid 4 to at least one of the transducer and non-transducer surfaces. The liquid supply system includes a reservoir 3 for accommodating the liquid, and at least one relatively rigid supply conduit 6 in contact with the substrate for supplying the liquid from the reservoir to the substrate.SELECTED DRAWING: Figure 1a

Description

[Technical field]

[0001] The present invention is directed generally to nebulizers for spraying liquids into small airborne droplets, and more particularly to nebulizers that use sonic energy to spray liquids. [Background technology]

[0002] The use of surface acoustic waves (SAW) to nebulize liquids has been proposed since the 1990s. See Kurosawa et al., "Surface Acoustic Wave Atomizers," Sensors and Actuators A:Physical, 1995, 50, 69-74. Since then, SAW nebulizers have found applications in a variety of fields, including the administration of active agents. Inhalation therapy is the most common treatment for asthma, chronic obstructive pulmonary disease (COPD), and other conditions associated with airflow limitation, such as obstructive bronchitis, emphysema, and cystic fibrosis. Extensive research and development has been conducted to improve the performance of SAW nebulization platforms in various application areas. These include fast drop ionization for interfacing to mass spectrometry (see "SR Heron et al., Surface Acoustic Wave Nebulization of Peptides as a Microfluidic Interface for Mass Spectrometry", Analytical Chemistry, 2010, 82, 3985-3989), nanoparticle synthesis (see "JR Friend et al., Evaporative Self-Assembly Assisted Synthesis of Polymeric Nanoparticles by Surface Acoustic Wave Nebulization", Nanotechnology, 2008, 19, 1253010), and pulmonary delivery (see AERajapaksa et al., Effective Pulmonary Delivery of Aerosolized Plasmid DNA Vaccines by Surface Acoustic Wave Nebulization", Respiratory Research, 2014, 15, 1).

[0003] Despite these ongoing efforts, the current state of the art has not advanced beyond the laboratory environment to address the issues surrounding the translation of a practical, commercially usable platform. These issues, which researchers often overlook, include cumbersome and complex fluidic chip-to-reservoir interfaces, poor flow rates, and pseudo-ejection of large droplets (often comprising a large proportion of the delivered volume), ultimately resulting in suboptimal nebulizers. These nebulizers are tailor-made to fit specific laboratory applications and are only accessible to specialized users, rather than practical, commercially viable platforms that can be reliably and easily used by end users.

[0004] Particular challenges in using such SAW spraying platforms relate to issues surrounding the liquids used and their supply to the device. A common approach is to supply the liquid using a wick located on the transducer surface of a piezoelectric substrate. An electroacoustic transducer, typically in the form of an interdigital transducer (IDT), is applied to the piezoelectric substrate by photolithographic techniques, allowing the SAW to propagate across the surface of the transducer. An arrangement using a supply wick is shown, for example, in US8991722 (Monash University).

[0005] However, the use of a wick at the surface of the transducer has undesirable consequences: SAW attenuation, heating of the interface material, and sensitivity of performance to the spatial location of the liquid on the device, especially when the acoustic energy is focused at the tip. Also, trailing liquid films with complex multi-step shapes present on the device during nebulization often produce large pseudo-droplets larger than 10 μm (>10 μm) and up to 100 μm in size. This is particularly undesirable for pulmonary drug delivery applications that require droplets on the order of 1 μm for deep lung deposition.

[0006] One proposed arrangement to avoid at least some of the above mentioned problems is shown in WO 2014 / 132228 (RMIT University), where the supply wick is in contact with the periphery of the piezoelectric substrate, minimising the energy losses associated with the wick and the supplied liquid being in contact with the transducer surface. Rather, the interaction of the peripheral SAW with the supplied liquid leads to the formation of a thin liquid layer from which atomisation is possible.

[0007] Another approach that has been proposed is to use conventional bulk acoustic waves (BAW) generated within the body of a piezoelectric substrate, rather than SAW, to atomize the liquid. US6679436 (Omron) describes an atomizer that uses conventional bulk waves for this purpose. Although a SAW platform is used, the SAW is not used for atomization but rather to sense the liquid (i.e. to detect whether liquid is present). Instead, the liquid is applied to the non-transducer surface of the piezoelectric substrate and bulk waves generated within the substrate are used to atomize the liquid.

[0008] A problem associated with prior art SAW and BAW platforms is the relatively low spray volume that can be produced with such platforms. Typically, SAW platforms have a spray volume of only about 0.1 ml / min, severely limiting the potential applications of such platforms.

[0009] Although atomization platforms using SAWs are generally considered to be the most efficient wave type, recent studies have shown that a combination of SAWs and surface-reflected bulk waves (SRBWs) provide superior liquid atomization (see Amgad R. Rezk et al., Hybrid Resonant Acoustics (HYDRA), Advanced Materials, 2016, 1970-1975). SRBWs are generated when a SAW on a transducer surface of a piezoelectric substrate is internally reflected between the transducer surface and a non-transducer surface on the opposite side of the substrate that is arranged in a parallel adjacent relationship to the substrate surface. Thus, SRBWs are generated at the same frequency as the SAWs. Thus, hybrid acoustic waves that combine both SAWs and SRBWs are generated due to their interrelationship and appear on both the transducer and non-transducer surfaces. The generation of SRBWs is optimized when the thickness of the substrate is at or close to the wavelength of the generated SAW.

[0010] International Publication No. WO2016 / 179664 (RMIT University) describes a spraying platform that uses hybrid acoustic waves in combination with SAW and SRBW to spray liquid. Liquid can be applied to the side or edge of a piezoelectric substrate using a wick or by directly immersing the edge of the substrate in a container of liquid. Hybrid acoustic waves (i.e., SAW and SRBW) then act to form a thin film of liquid on both the IDT and non-IDT surfaces of the substrate. However, the combined SAW and SRBW spraying platform still has similar concerns as those found in SAW-only spraying platforms, because in one of the above-mentioned embodiments, a wick is used that contacts the substrate.

[0011] These and other SAW nebulizer systems also suffer from problems with performance reliability, reproducibility, efficiency, and droplet distribution. In particular, systems utilizing single crystal tips are prone to failure due to overheating and pyroelectric failure. Some configurations also require the tip to be in contact with the liquid sample at all times. There is room for improvement in the performance reliability and efficiency of such devices. Furthermore, achieving appropriate operating parameters, including but not limited to droplet size, geometric standard deviation (GSD) of droplet distribution, stabilization period (i.e., time of use), volumetric nebulization rate, and fine particle fraction, for the administration of various active pharmaceutical ingredients (APIs) remains a significant challenge.

[0012] The above description of the background art is included to explain the context of the present invention and should not be construed as an admission that the background art was known or part of the common general knowledge as of the priority date of any claim in the specification.

[0013] The term "acoustic energy" is used herein to refer to traveling and standing surface acoustic waves (SAWs), bulk acoustic waves (BAWs), including surface reflected bulk waves (SRBWs), and combinations of these waves, particularly the combination of SAWs and SRBWs.

[0014] The term "liquid" is used herein to refer to a pure liquid or a liquid mixture containing functional or therapeutic substances such as pharmaceuticals, plasmid DNA, peptides, fragrances, etc.

[0015] There is a need for an acoustic nebulizer that addresses one or more of the shortcomings associated with prior art acoustic nebulizers, or at least provides an alternative. Summary of the Invention

[0016] With this in mind, according to one aspect of the present invention, there is provided a nebulizer comprising: Housing and at least one piezoelectric substrate contained within the housing, the piezoelectric substrate having a transducer surface on which at least one electro-acoustic transducer is disposed for generating acoustic energy within the substrate, and an opposing non-transducer surface; a liquid supply system for supplying liquid to at least one of the transducer surface and the non-transducer surface; Including, The liquid supply system includes a reservoir for containing the liquid, and at least one relatively rigid supply conduit in contact with the substrate for supplying the liquid from the reservoir to the substrate.

[0017] The delivery conduit may be in the form of a point or needle and, preferably, the delivery conduit may be formed from an acoustically reflective material.

[0018] The liquid may be gravity fed from the reservoir through the supply conduit, or alternatively, the liquid may be transferred from the reservoir to the substrate via an active pumping system, for example a syringe or peristaltic pump.

[0019] The liquid supply system may further include a flow regulator for providing a steady flow of liquid from the system. The flow regulator may include a liquid outlet passage through which liquid can pass, and an air inlet passage connected to the reservoir.

[0020] An internal chamber may be connected to the flow regulator, the internal chamber having a peripheral opening within which a peripheral tip of the supply conduit is received, and liquid may pass between the peripheral opening and the peripheral tip of the supply conduit by capillary action.

[0021] The substrate may be supported on a displaceable mount to control contact of the substrate with the supply conduit. The mount may, for example, include a pivot support at one end and an opposing end supported by a resilient member. Alternatively, the mount may be supported on a cantilever.

[0022] According to another aspect of the present invention, a nebulizer for spraying liquid droplets is provided, comprising: Housing and at least one piezoelectric substrate contained within the housing, the piezoelectric substrate having a transducer surface on which at least one electro-acoustic transducer is disposed for generating acoustic energy within the substrate, and an opposing non-transducer surface; a flexible material in contact with at least a portion of the outer circumferential surface of the at least one piezoelectric substrate; a liquid supply system for supplying liquid to at least one of the transducer surface and the non-transducer surface; Including, The liquid supply system includes a container for containing the liquid and at least one supply conduit for supplying the liquid from the container to the substrate.

[0023] The flexible material may include adhesive tape, silicone rubber, and thermal paste, or a combination thereof.

[0024] The nebulizer may further include a control means for controlling the size of the atomized droplets. The control means may include at least one baffle disposed in substantially parallel adjacent relationship with at least one of the transducer surfaces. The substrate may be supported within a housing. The baffle(s) included in the droplet size control means may be provided by an inner housing wall disposed in parallel adjacent relationship from at least one of the substrate surfaces. In another embodiment, the control means for controlling the size of the atomized droplets may alternatively be provided by active substrate baffle action.

[0025] The housing may further include an inlet opening, and the container may include a neck receivable in the inlet opening to enable the liquid held within the container to be gravity fed to the at least one substrate.

[0026] A nebulizer according to the invention may include at least two of the substrates arranged in spaced apart parallel adjacent relationship. The droplet size control means may further include controlling the size of the atomized droplets by presetting the spacing between the substrates to control a thickness of a meniscus of the liquid dispensed between adjacent substrate surfaces. Alternatively, the droplet size control means may include controlling the size of the atomized droplets by presetting the spacing of the substrates from an inner wall of the housing to control a thickness of a meniscus of the liquid dispensed between adjacent substrate surfaces and the inner wall.

[0027] The generated acoustic energy may include a surface acoustic wave (SAW) propagating on the transducer surface of the at least one substrate. The acoustic energy may include a surface-reflected bulk wave (SRBW) reflecting between the transducer surface and the non-transducer surface of the at least one substrate. In one embodiment, the acoustic energy may include a combination of a surface acoustic wave (SAW) and a surface-reflected bulk wave (SRBW). The surface acoustic wave (SAW) may include standing waves, traveling waves, and combinations thereof. The surface-reflected bulk wave (SRBW) may include standing waves, traveling waves, and combinations thereof. As described above, an SRBW is generated when a SAW on a transducer surface of a piezoelectric substrate is internally reflected between the transducer surface and a non-transducer surface on the opposite side of the substrate that is disposed in a parallel adjacent relationship to the substrate surface (i.e., the other side of the substrate). Thus, an SRBW is generated at the same frequency as a SAW. Hybrid acoustic waves combining both SAW and SRBW can be generated due to their interrelationship and appear on both transducer and non-transducer surfaces.

[0028] As mentioned above, the liquid supply system may supply liquid to at least one of the transducer surface and the non-transducer surface. In view of this and the fact that sound waves may appear on both the transducer surface and the opposing non-transducer surface, it should be understood that the liquid sample may be sprayed from the transducer surface, the non-transducer surface, or both the transducer surface and the non-transducer surface. In one embodiment, the liquid is sprayed from the transducer surface. In another embodiment, the liquid is sprayed from the non-transducer surface. In another embodiment, the liquid is sprayed from both the transducer surface and the opposing non-transducer surface.

[0029] The piezoelectric substrate and electroacoustic transducer according to the invention are preferably also used to sense a liquid mass on said at least one substrate. Unlike US6679436 (Omron) which uses surface waves or SAW for sensing, in the present invention, bulk waves or BAW generated on the same substrate are used for sensing.

[0030] The electroacoustic transducer for a nebulizer according to the present invention may be an interdigital transducer (IDT), and the at least one piezoelectric substrate may be formed from lithium niobate (LiNbO3).

[0031] In one embodiment, at least a portion of the non-transducer surface may further include a coating comprised of at least one metal. In one embodiment, at least a portion of the transducer surface at the distal end of the substrate may further include a coating comprised of at least one metal. The at least one metal may be titanium, gold, aluminum, chromium, or a combination thereof.

[0032] The piezoelectric substrate has a thickness that is at or near the wavelength of the SAW propagating on the transducer surface, thereby optimizing generation of an SRBW within the substrate.

[0033] In the nebulizer according to the present invention, the liquid can be nebulized to form droplets having a size ranging from 0.1 to 100 μm, and the liquid can be nebulized at a spray rate of up to 10.0 ml / min.

[0034] The mount may include a shelf on which the substrate rests, the shelf including one or more gaps to prevent liquid creep along the substrate.

[0035] According to a preferred embodiment of the nebulizer according to the invention, the housing may be in the form of a cartridge having external electrical contacts connected to the at least one electroacoustic transducer and an integrated liquid supply system.

[0036] In another aspect of the invention, a method of nebulizing a liquid using the nebulizer described above is provided.

[0037] The method may include the step of aerosolizing a liquid to form droplets having a size in the range of 0.1 to 100 μm. Small droplet sizes of 1 to 5 μm are ideal for inhaled therapeutic substances. However, it will be appreciated that larger droplet sizes of over 10 μm may be formed as required for other applications including fragrances, cosmetics, insecticides, paints or preservatives.

[0038] The method may include spraying the liquid at a spray rate of up to 10.0 ml / min.

[0039] Advantageously, the method may include the step of spraying a liquid containing functional or therapeutic substances such as pharmaceuticals, plasmid DNA, RNAi, peptides, proteins and cells, or non-therapeutic substances such as fragrances, cosmetics, pesticides, paints or preservatives.

[0040] The use of both transducer and non-transducer surfaces for fluid delivery and nebulization in the nebulizer of the present invention not only provides much higher nebulization rates (1 ml / min or more compared to typical SAW nebulization rates of 0.1-0.2 ml / min), but also avoids undesirable heating due to viscous dissipation of acoustic energy when it couples with materials that typically have poor acoustic matching properties, materials typically used in previous nebulizer configurations for fluid transmission (glass, wick, PDMS, etc.). In addition, the preferred configuration of the nebulizer of the present invention preferably reduces contact of chemicals and sensitive samples with the electroacoustic transducer. This has the advantage of protecting the transducer electrodes from harsh chemicals, as well as protecting any sensitive biological samples from the strong electric fields generated by the electrodes.

[0041] It will be convenient to further describe the invention with reference to the accompanying drawings, which show a preferred embodiment of a nebulizer according to the invention. Since other embodiments are possible, the particularity of the accompanying drawings should not be understood as superseding the generality of the preceding description of the invention. [Brief description of the drawings]

[0042] [Figure 1a] FIG. 2 is a side cross-sectional view of a nebulizer according to one embodiment of the present invention. [Figure 1b] FIG. 13 is a close-up view of a liquid delivery system comprising a tip or needle according to one embodiment. [Figure 1c] FIG. 2 is a detailed side view of a nebulizer according to one embodiment of the present invention. [Figure 1d] FIG. 2 is a detailed cross-sectional side view of another embodiment of a nebulizer according to the present invention. [Figure 1e] FIG. 2 is a side cross-sectional view of another embodiment of a nebulizer according to the present invention. [Diagram 2] FIG. 2 is a perspective view of a platform holding a piezoelectric substrate for a nebulizer according to the present invention. [Figure 3a] FIG. 2 is an orthogonal view of the transducer surface of a nebulizer according to the present invention. [Figure 3b]3b is an orthogonal view of the transducer surface of another embodiment of the nebulizer described above, with the peripheral surface of the substrate highlighted.As described above, a flexible absorbent material may be in contact with at least a portion of the peripheral surface of the substrate surface highlighted in FIG. [Figure 3c] FIG. 2 is an orthogonal view of the transducer surface of another embodiment of the nebulizer described above, highlighting the coating on the distal end of the transducer surface and areas suitable for patterning. [Figure 3d] FIG. 2 is a representation of a nebulizer as described above, in which the non-transducer surfaces of the nebulizer are partially coated. [Figure 3e] FIG. 2 is an orthogonal view of the transducer surface of another embodiment of the nebulizer described above, highlighting the coating on the distal end of the transducer surface of the substrate. [Figure 4a] FIG. 2 is a side cross-sectional view of another embodiment of a nebulizer according to the present invention. [Figure 4b] FIG. 2 is a side cross-sectional view of another embodiment of a nebulizer according to the present invention. [Figure 5a] 4 is a graph of the size distribution of ejected droplets of a nebulizer according to the present invention without a baffle. [Figure 5b] 4 is a graph of the size distribution of ejected droplets of a nebulizer according to the present invention having a baffle. [Figure 6] Graph showing texture detection of Humalog (insulin medication) as a function of frequency. [Figure 7] 13 is a graph showing spray distribution data for a nebulizer according to one embodiment of the present invention, in which the non-transducer surface of the substrate is coated with titanium and gold. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] 1a and 1c, there is shown a first preferred embodiment of a nebulizer according to the present invention. The nebulizer comprises a mount 1 supporting a piezoelectric substrate 2. The piezoelectric substrate 2 has a transducer surface 2a on which an electro-acoustic transducer (not shown) in the form of an interdigital transducer (IDT) is disposed. The substrate 2 further comprises a non-transducer surface 2b disposed in parallel adjacent relationship to the transducer surface 2a.

[0044] The nebulizer further comprises a liquid container 3 in which a liquid 4 to be nebulized by the nebulizer is contained. The container 3 may be in the form of a bottle or vial with a threaded neck 3a which may be screwed into a threaded inlet opening 5 in a housing (not shown). The nebulizer is shown in its use state in Figures 1a and 1c. In use, the liquid 4 may be gravity fed from the container 3 via a relatively rigid feed conduit in the form of a tip or needle 6. A liquid meniscus 7 is formed at the end of the tip or needle 6 on the transducer surface 2a (Figure 1b). RF power is provided to the IDT via electrical contacts 8. This generates a surface acoustic wave (SAW) at the transducer surface 2a which then generates a surface reflected bulk wave (SRBW) which reflects between the transducer surface 2a and the non-transducer surface 2b. A unique hybrid wave configuration of the SRBW in combination with the SAW draws the liquid 4 from the liquid meniscus 7 beyond the transducer surface 2a. If an accumulation of liquid 4 occurs at the edge of the transducer surface 2a, the sonic energy draws the liquid 4 near the edge of the substrate 2 and directs it toward the non-transducer surface 2b of the substrate 2. The liquid 4 may also be sprayed at the non-transducer surface 2b. A gravity-fed mechanism provides a continuous, self-regulating stream of liquid to fill the needle or tip 6.

[0045] More specifically, a feed pump, gravity feed or capillary action in the tip or needle 6 of the present invention simply acts to fill it. The liquid 4 is then drawn by the acoustic waves to the surface of the substrate 2 as shown in FIG. 1b. It is therefore preferred that the liquid delivery system, i.e. the tip or needle 6, is in contact with the substrate 2. This is in contrast to capillary actuation of liquid delivery to a feed channel etched in the substrate in WO 2012 / 096378 (Panasonic Corporation). By drawing the liquid from the tip or needle 6 to the substrate 2 by the acoustic waves, only the amount of liquid to be sprayed is drawn into the device, thus avoiding overflow of liquid.

[0046] The material selection for the tip or needle 6 should preferably include an acoustically reflective material. An acoustically absorbing material has a tendency to absorb and attenuate the acoustic wave energy on the substrate 2. Such materials may include metals, polymers, or ceramic materials.

[0047] The housing further includes at least one baffle 9. The baffle 9 may, for example, be formed from a wall of the housing and disposed in spaced-apart and generally parallel adjacent relationship to the transducer surface 2a. Early nebulizer designs attempted to control and maintain the size uniformity of the atomized droplets using meshes. However, such meshes tend to clog. In contrast, the baffle 9 provides a simpler means of controlling the size uniformity of the droplets. Larger droplets 11, having a size on the order of 10 μm to 100 μm, are ejected from the substrate surface 2a with more momentum than smaller droplets. This is due to the angle at which the acoustic energy couples with the liquid 4 (known as the Rayleigh angle). This causes the droplets to be ejected so as to be atomized at the same angle. Such larger droplets 11 then impact the surface of the baffle 9 and are redirected towards the substrate surface 2a. Here, the droplets 11 are re-fed to the existing liquid supply from the container 3. Thus, the liquid that was part of the returning droplets 11 is again atomized. On the other hand, smaller droplets 10, having a size on the order of approximately 1 μm, have significantly less momentum and therefore do not reach the surface of the baffle 9. Instead, the small droplets 10 are entrained in the airflow from the nebulizer. A similar droplet size control process occurs between the non-transducer surface 2b and the corresponding baffle surface 9 adjacent to the non-transducer surface 2b.

[0048] FIG. 1d shows another embodiment of a nebulizer according to the invention, utilizing at least two piezoelectric substrates 12, 13 supported in a stacked configuration within the nebulizer. Three or more piezoelectric substrates may be stacked in a parallel and adjacent position within the nebulizer. Each piezoelectric substrate 12, 13 is configured similarly to the embodiment shown in FIG. 1a and FIG. 1c, with an electroacoustic transducer disposed on a transducer surface 12a, 13a of each substrate 12, 13. This allows acoustic energy to be generated within each substrate, drawing atomized liquid provided to both the substrate surface 12a, 13a and the adjacent parallel non-substrate surface 12b, 13b of each substrate 12, 13. The housing also includes a lower baffle 9a, which is disposed parallel and adjacent to the transducer surface 13a of the lower substrate 13 to aid in droplet size control as described above. A similar effect occurs between the non-substrate surface 12b of the upper substrate 12 and the baffle 9b facing that surface. In this embodiment, the arrangement of the transducer surfaces 12a, 13a and non-transducer surfaces 12b, 13b of the two substrates 12, 13 is not critical and these surfaces may be interchanged as long as they are parallel and adjacent to each other. Nevertheless, such a configuration provides an additional means for controlling the uniformity of the droplet size. Similarly, liquid is trapped in the interstitial space 14 between the two substrates 12, 13, between the transducer surface 13a of the lower substrate 13 and the lower baffle surface 9a, and between the non-transducer surface 12b of the upper substrate 12 and the upper baffle surface 9b. The thickness of the liquid meniscus 7 is an important parameter in controlling the droplet size. Thus, by adjusting the relative spacing between each substrate 12, 13 and the baffle surfaces 9a, 9b, the thickness of the meniscus can be controlled, which provides uniformity in the size of the sprayed droplets. Thus, such a configuration allows the droplet size to be controlled by adjusting the spacing. It is also envisioned to have multiple spacings to obtain multiple droplet sizes.

[0049] FIG. 1e illustrates another embodiment of a nebulizer according to the present invention, utilizing at least two piezoelectric substrates 12, 13 supported in a stacked configuration within the nebulizer. Similar to the embodiment described in FIG. 1d, liquid is trapped in the interstitial space 14 between the two substrates 12, 13. Unlike FIG. 1d, the liquid meniscus 7 need not be in contact with both substrates 12 and 13. Furthermore, the tip or needle 6 may in one embodiment be in direct contact with the surface of one of the substrates 12 to deliver the liquid 6. In another embodiment, the tip or needle 6 may not be in contact with the surface of the substrate 12, but may be positioned such that the liquid 6 is delivered in contact with the surface of the substrate 12. It is envisioned that the at least two piezoelectric substrates 12, 13 may be the same or different. For example, one or more substrates may be patterned as described in more detail below to provide further control of the output parameters of the nebulizer.

[0050] Further, referring to the configurations of Figures 1d and 1e, for example, higher spray volumes may be provided since there are multiple substrate surfaces on which spraying may occur. Adjacent substrate surfaces may also act as active baffles, where larger spurious droplets ejected from one substrate surface are collected on the surface of an adjacent substrate and resprayed until smaller droplets are produced. This approach may be considered an active substrate baffle action, rather than a passive physical baffle provided by the inner wall of the housing. This system may be enhanced by promoting standing waves or regions of standing waves using the techniques described above.

[0051] Also, the same piezoelectric substrate 2, 12, 13 and IDT can be triggered at a low frequency (approximately 3.5 MHz for a 500 μm thick substrate) corresponding to the fundamental thickness mode (BAW) of the substrate to employ the sensing function. The reason for using the thickness mode for sensing is that the single crystal used is naturally 10 4 〜10 6The single crystal has a high quality factor Q of the order of 10 ng. Examples of single crystals include, but are not limited to, 128YX lithium niobate piezoelectric crystals. Thus, such a platform can simultaneously perform both efficient nebulization and efficient mass detection with a detection limit down to 10 ng. Both functions can be achieved with the same electrode pattern, unlike other known devices that incorporate different electrode patterns for different microfluidic functions. Thus, the nebulizer according to the present invention can be added with the function of detecting the residual mass during nebulization. The purpose is to measure the actual dose administered to the user by subtracting it from the total dose delivered.

[0052] In the above-described embodiment of Fig. 1a and Fig. 1c, the liquid 4 is gravity-fed to the tip or needle 6. The tip or needle 6 presses the end of the transducer surface 2a to bring the liquid 4 into contact with the transducer surface 2a where the liquid 4 may be atomized into droplets 10, 11. Robust contact between the tip or needle 6 is achieved by displacing the mount 1 towards the tip or needle 6, which is preloaded and exerts a constant pressure under displacement (not shown). In one embodiment, the preload is achieved, for example, by fixing the mount 1 to a cantilever or by configuring the mount 1 to have an arrangement of a pivot 15 fixed to a housing (not shown) and a resilient member in the form of a spring 16. The displacement of the mount 1 caused by pressing the tip or needle 6 against the substrate 2 may bring the end of the tip or needle 6 into contact with the transducer surface 2a at a constant pressure and may form and sustain a meniscus 7. This meniscus 7 provides a pressure equal to the pressure of the sealed container 3. This prevents the liquid from freely flowing from the container 3 onto the substrate. The ability of the mount 1 to displace and apply pressure means that a rigid tip or needle 6 can be effectively used for direct contact with the substrate. Referring to FIG. 1b, the tip or needle resonates with the acoustic energy, which can draw the liquid 4 from the tip or needle 6 and beyond the substrate surface 2. During spraying of the liquid 4, the meniscus 7 becomes smaller due to the reduction of the liquid 4. The negative pressure that is then generated draws more liquid 4 through the tip or needle 6, replenishing the meniscus 7. If the relative pressure in the container 3 is low enough due to the outflow of the liquid 4 through the tip or needle 6, air bubbles can enter the container 3 via the inlet hole 17 to balance the pressure and the liquid 4 can be drawn by the tip or needle 6. This process continues until the container 3 is empty. It is envisioned that multiple tips or needles can be used to increase the flow rate and improve the reliability of the system. However, it is also envisioned that a pressure relief valve can be used to provide a controlled flow of liquid to the transducer surface 2a. It is further envisaged that the edge of the substrate 2 may be submerged in the meniscus, providing liquid through closely spaced orifices.Alternatively, it is envisioned that liquid may be actively supplied to the substrate surface 2a using an active pumping system, such as a syringe or peristaltic pump. In situations where liquids having high surface tension and / or high viscosity need to be delivered to the transducer surface 2a, an active pumping system may be suitable.

[0053] The flow regulator 19 may also be used in combination with the gravity feed system, adjacent orifice, or active pump system described above. It is also envisioned that the flow regulator 19 functions in a manner similar to that of a fountain pen. Such an arrangement is shown in FIG. 1a, where the fluid in the container 3 flows into the internal chamber 18 through the flow regulator 19. The flow regulator 19 has a liquid outlet passage 20 through which the liquid 4 can pass, and an air inlet passage 21 connected to the container 3. The flow regulator 19 thus provides a steady supply of the liquid 4, which balances the air pressure outside and inside the container 3. Without the flow regulator 19, the liquid 4 would be disturbed by the release of air bubbles that invade through the inlet passage 21. The liquid 4 is delivered to the internal chamber 18. The internal chamber 18 has a peripheral opening 22 that connects to the tip or needle 6 and in which the tip or needle 6 is received. The tip or needle 6 is therefore always wetted with the liquid 4.

[0054] The electrical contact end of the substrate 2 is pressed against the mount 1 in direct contact to dissipate localized heating that may damage the substrate 2. Such pressing may be accomplished, for example, by applying pressure via a contact cantilever 23 in which a wide electrical contact 8 is embedded. The wide electrical contact 8 also mitigates damaging arcing between the electrical contact 8 and the substrate 2 under the high voltages generated during spraying. Pressure on the contact cantilever 23 base may be applied, for example, via a magnetic effect or by using a screw 24 to depress a spring washer 25. Alternatively, pressure may be applied via a spring-loaded electrical contact. It is further envisioned that a conductive material may be bonded directly to the IDT instead of the electrical contact. A heat sink surface (not shown), which may be incorporated into the mount 1, may also be utilized by pressing the tip or needle 6 against the parallel substrate 2 and keeping it in contact with the heat sink during spraying to cool the substrate 2. The heat sink may also feature a shape that contacts the spray end of the substrate 2 to hold a small amount of excess liquid. This increases the robustness of the system while spraying is taking place. The mount 1 may be made from a conductive material, such as a metal, which allows for the immediate discharge of excess pyroelectric induced charges, thereby reducing the risk of damaging arcing through the substrate 2 and increasing the lifespan of the substrate 2.

[0055] 2, mount 1 holds substrate 2 along its side edges on a narrow shelf 26 so that if any wetting occurs between mount 1 and substrate 2, the acoustic energy is not attenuated as it travels along substrate 2. A gap 27 is also provided along narrow shelf 26 of mount 1. Gap 27 prevents liquid 4 from creeping up substrate 2 between its contacts and mount 1.

[0056] 3(a), the transducer surface 2a has surface features such as a shield 28, a bend 29 in the main IDT bar 30, and a reflective bar 31 at the electrical contact end 32. The reflective bar 31 impedes the progression of acoustic energy and helps reflect and absorb potentially damaging acoustic energy at the electrical contact end 32. The reflected acoustic energy assists in atomizing the liquid at the spray end 33 of the substrate 2. An exposed surface 34 exists between the end of the main IDT bar 30 and the spray end 33 of the device to reduce contact between the sprayed liquid and the IDT 35.

[0057] In another embodiment, the nebulizer described above may further comprise a flexible absorbent material in contact with at least a portion of the outer peripheral surface of the substrate. For example, the outer peripheral surface of the substrate is highlighted as hashed region 40 in FIG. 3(b). It should be understood that the flexible absorbent material may be in contact with at least a portion of the outer peripheral surface 40 highlighted in FIG. 3(b). Surprisingly, it has been discovered that the durability of the tip may be improved by adding a flexible material in contact with at least a portion of the outer peripheral surface of the substrate. Without wishing to be bound by theory, it is believed that the addition of a flexible material may distribute or reduce excessive vibrations in and / or on the tip. It is further believed that the addition of a flexible material may prevent overheating or localized overheating in and / or on the substrate. This reduces the failure rate of the substrate and provides improved reliability and use from a nebulizer that is free of damage and failure. For example, suitable flexible materials may include pastes, tapes, or flexible solids. In one embodiment, the flexible material is an adhesive tape. In one embodiment, the flexible material is silicone rubber. In one embodiment, the flexible material is thermal paste. In one embodiment, the compliant material comprises a portion of the housing that is in contact with the periphery of the tip.

[0058] In one embodiment, the flexible absorbent material may be in contact with at least a portion of the periphery of the distal end of the substrate. In one embodiment, the flexible absorbent material may be in contact with at least a portion of one or more sides of the peripheral surface of the substrate. In one embodiment, the flexible absorbent material may be in contact with a portion of one or more sides and a portion of the distal end of the substrate. In particular, the placement around at least a portion of the peripheral surface allows acoustic radiation in the spray region of the substrate to be sufficient to achieve spraying.

[0059] It has further been found that coating at least a portion of the non-transducer side of the substrate can change the wave reflection and standing wave ratio (SWR). In one embodiment, the coating can be comprised of one or more metals. In one embodiment, the coating is formed from titanium, gold, aluminum, chromium, and combinations thereof. The inventors have surprisingly found that coating at least a portion of the non-transducer surface of the substrate with one or more metals can reduce overheating. The inventors have also surprisingly found that coating at least a portion of the non-transducer surface of the substrate can provide some control and / or enable tuning of the standing and traveling wave components in SAW, SRBW, and combinations thereof. Surprisingly, full or partial coating has been found to affect the traveling and standing wave components present on and within the substrate. A representative example is shown in FIG. 3(d), where the non-transducer surface 43 of the substrate is partially coated 42. The standing wave ratio can be further altered by adjusting parameters such as the hardness, thickness, and / or roughness of the coating. It has been observed that adjusting the standing wave ratio between one and infinity improves the stability of the substrate and the amount of atomization. As an example, atomization distribution data is shown in FIG. 7, where the non-transducer substrate surface was coated with titanium and gold. The coating resulted in a narrower overall droplet distribution as measured by the geometric standard deviation (GSD). In comparison, when an uncoated tip is used, two distinct peaks are typically observed in the droplet distribution of the atomized fluid. This is believed to be due to the promotion or preference of traveling wave components over standing wave components in the system. Conversely, when the tip is coated, it is observed that the standing wave component is promoted or preferred over the traveling wave component. By varying the ratio of traveling wave components to standing wave components, parameters including droplet size, geometric standard deviation, etc. can be controlled or adjusted. These parameters are further described below. In one or more embodiments, the nebulizers described above may utilize traveling wave components, standing wave components, and / or combinations thereof.In one or more further embodiments, the nebulizer described above may utilize a standing wave component of a SAW, a standing wave component of a SRBW, a traveling wave component of a SAW, a traveling wave component of a SRBW, an array, and combinations thereof.

[0060] In addition to coatings applied to non-transducer surfaces, the inventors have surprisingly found that overheating can be reduced by coating at least a portion of the transducer surface of the substrate with one or more metals. In particular, the inventors have found that when at least a portion of the transducer surface further comprises a coating at the distal end of the substrate, tip failure due to overheating or pyroelectric failure is reduced or eliminated, providing a more efficient and robust system. In one embodiment, the coating on the transducer surface can be comprised of one or more metals. In one embodiment, the coating is formed from biocompatible metals including titanium, gold, and combinations thereof. Representative examples are shown in Figures 3(c) and 3(e). That is, the entire transducer surface of the substrate comprises a coating 41 (Figure 3c); and at least a portion of the transducer surface of the substrate comprises a coating 44 at the distal end of the substrate (Figure 3e).

[0061] In another embodiment, the nebulizer described above may further comprise patterning of a conductive material on a portion of the substrate surface. As used herein, the terms "patterning" and "patterned" and variations thereof refer to techniques such as photolithography that transfer a geometric pattern onto a given substrate. Such techniques are typically used for patterning in the chip industry. Generally, a coating is applied, particularly a metal coating as described above, and then the surface is patterned by lithography or other means. In one embodiment, the transducer substrate surface is patterned. In another embodiment, a non-transducer substrate surface is patterned. Surprisingly, it has been found that the addition of patterning (on areas of the substrate other than the functional area of ​​the transducer surface) can assist in dissipating or reducing localized overheating and / or pyroelectrically induced charges. It is further understood that the non-transducer surface of the substrate may alternatively or additionally be patterned. Figure 3(c) highlights the functional areas of the transducer surface of the substrate (including main IDT bar 30, IDT 35, shield 28, flexure 29, reflective bar 31). One of the areas of the transducer surface of the substrate suitable for patterning includes coated surface 41, highlighted in grey in Figure 3(c). Those skilled in the art will appreciate that such patterning may be placed on any area of ​​the surface of the chip that still allows the device to function as a nebulizer.

[0062] It has also been found that tuning of the standing wave ratio can also be achieved by arranging multiple sets of IDTs such that the resulting waves interact. As an example, it is envisioned that patterning the IDTs can disrupt destructive acoustic waves and improve the reliability of the resulting chip, for example by reducing undesirable overheating. Furthermore, in an embodiment, the substrate may be patterned or coated to provide distinct regions in which either standing waves or traveling waves are promoted. It is envisioned that such a configuration provides further tunability in the range of output parameters of the atomized liquid.

[0063] Although embodiments utilizing a needle or tip have been described, further embodiments are envisioned in which at least one delivery conduit may include a wick or microchannel. The selection of a particular delivery conduit may depend in part on how the conduit operates in combination with other features of the nebulizer system.

[0064] Figures 4a and 4b show another preferred embodiment of the nebulizer according to the invention. In this configuration, the substrate 2 and other major components are integrated into a single integral housing or cartridge 36. The cartridge 36 may interface with an external housing featuring the appropriate electrical system and flow chamber of the nebulizer (not shown) and may be used as a single or multi-dose cartridge 36 that is disposable after use. The container 3 may be formed from a cavity in the cartridge 36. One side of the container may be a deformable blister or button 37 that can be depressed. This may function to displace liquid inside the container to inject liquid into the needle or tip 6, or may deposit the entire amount of liquid 4 onto the substrate 2 to form a meniscus 7. Other means of displacing the liquid 4 are also possible, for example a syringe plunger. Figure 4a shows the system before the blister 37 is depressed to deposit the liquid 4. And Figure 4b shows the system after the blister 37 is depressed to cause the deposition of the liquid 4. RF power may be supplied to the substrate via exposed spring contacts 38 connected to wide electrical contacts 8 in contact with the substrate 2. The exposed spring contacts 38 allow the cartridge 36 to interface with an external body that may house a suitable nebulizer electrical system and flow chamber (not shown). Peripheral parallel surfaces surrounding the substrate 2 act as baffle surfaces 9 to control droplet size and recirculate excess liquid 4. The cartridge may be protected by a seal 39 that may be broken or removed before the liquid 4 is nebulized or when the cartridge 36 interacts with the nebulizer external body. The cartridge may incorporate any combination of features described and shown in Figures 1a, 1c, 1d, 1e, 2, and 3a, 3b, 3c, or 3d.

[0065] The presented circuit is a small handheld circuit that operates at high frequency (10 MHz). Its simplicity is the main reason that it overcomes the barrier of miniaturization of alternative radio frequency (RF) circuits due to their bulkiness. In typical RF circuits, the most important components commonly and intuitively rely on digital data and programming to track the target frequency and trigger various accessories such as sensor drivers, power buttons, etc. Unlike such RF circuits, the present circuit utilizes a single frequency that is robust, stable, and constant, regardless of the nature of the load placed on the circuit. The present circuit can also sense the user's breathing pattern to drive the nebulizer and / or be actuated by a trigger button. The present circuit maintains only analog data transfer and actuation for the entire circuit.

[0066] The circuit is small and compact, yet offers dual triggering methods: 1- continuous or toggle button press, or 2- "smart" triggering via user inhalation. The trigger time is pre-determined to accommodate long user inhalations, thus allowing for precise dosing time and known dosage.

[0067] The above counter-intuitive circuit design approach, utilizing analog data transfer operating in the RF domain, allows the circuit to be powered by a small 11.1V (3-cell) lithium polymer battery.

[0068] Figure 5a shows the droplet size distribution jetted without the use of a baffle 9. The graph shows that the majority of the droplets have a size in the range of 10 μm to 100 μm. Figure 5b shows the droplet size distribution jetted with the use of a baffle 9. The graph shows that larger droplets between 10 μm and 100 μm in size are minimized.

[0069] For sensing, an optically flat single crystal substrate is used. 4 〜10 6This allows for bulk (e.g. Lamb) wave resonance with a large quality factor Q of the order of 100 s. Thus, very small mass loadings on the surface of the substrate produce detectable frequency shifts, allowing mass detection of samples down to a sensitivity of 10 ng. This is shown in the graph in Figure 6, which shows the mass detection of Humalog (insulin drug). The graph shows a linear frequency shift with increasing mass, with a sensitivity of 100 ng.

[0070] SAW nebulizers have found applications in a variety of areas, including the administration of active agents. Inhaled medications are the most common treatment for asthma, chronic obstructive pulmonary disease (COPD), and other conditions associated with airflow limitation, such as obstructive bronchitis, emphysema, and cystic fibrosis. For example, corticosteroids, bronchodilators, and β2 agonists are typically administered by inhalation to treat asthma, COPD, and other respiratory diseases. It is envisioned that the above-mentioned nebulizers may be used in combination with a range of possible active agents. Suitable active agents include, but are not limited to, corticosteroids (such as fluticasone, budesonide, mometasone, beclomethasone, and ciclesonide), bronchodilators (such as salmeterol or albuterol, formoterol, vilanterol, levalbuterol, and ipratropium). For example, albuterol, also called salbutamol or ventolin, is a beta 2 agonist and short-term bronchodilator that opens the middle and large airways of the lungs. Ipratropium, also called ipratropium bromide, is a muscarinic antagonist (a type of anticholinergic drug) that opens the middle and large airways of the lungs. Budesonide, also called BUD, is a type of corticosteroid used in the long-term management of asthma and chronic obstructive pulmonary disease (COPD). In one embodiment, the nebulizer described above is suitable for the delivery of albuterol. In one embodiment, the nebulizer described above is suitable for the delivery of ipratropium. In one embodiment, the nebulizer described above is suitable for the delivery of budesonide.

[0071] The above-described nebulizers advantageously provide reliable, efficient, and accurate delivery of active agents. The resulting nebulized liquid may be characterized by one or more parameters. It is understood that each active agent has different physicochemical properties. It is further understood that various parameters of the above-described nebulizers may be optimized for delivery of a given active agent, including droplet size (microns), geometric standard deviation (GSD), volumetric spray volume, stabilization period (i.e., time of use), percentage of API administered, trajectory loss, and fine particle fraction.

[0072] In one aspect, the nebulizer provides control over the droplet size of the spray liquid. In particular, the droplet size of the spray liquid can be optimized for a given active agent. In one embodiment, the nebulizer provides a spray liquid with a droplet size in the range of 0.1 to 100 μm, preferably in the range of 0.1 to 10 μm, preferably in the range of 0.5 to 7.5 μm, more preferably in the range of 1 to 5 μm, and even more preferably in the range of 2 to 4 μm. In one embodiment, the nebulizer provides a spray liquid with a droplet size of less than 10 μm (<10 μm), preferably less than 8 μm (<8 μm), preferably less than 6 μm (<6 μm), preferably less than 5 μm (<5 μm), and preferably less than 3 μm (<3 μm).

[0073] In one aspect, the nebulizer described above provides control of the geometric standard deviation (GSD) of droplets of the spray liquid. In particular, the GSD of the spray liquid can be optimized for a given active agent. In one embodiment, the nebulizer described above provides a spray liquid with a GSD of less than 10 μm (<10 μm), preferably less than 8 μm (<8 μm), preferably less than 6 μm (<6 μm), preferably less than 5 μm (<5 μm), preferably less than 3 μm (<3 μm), preferably less than 2.5 μm (<2.5 μm), preferably less than 2.1 μm (<2.1 μm). In one aspect, the nebulizers described above provide control over the stabilization period (i.e., time of use). Advantageously, the nebulizers described above provide a reduced stabilization period (i.e., time of use). A shorter or reduced stabilization period reduces delay time for use, improves efficiency, reduces sample or fluid loss, and improves dosage and administration accuracy of the active agent. In particular, the stabilization period may be optimized for a given active agent. In one embodiment, the nebulizers described above provide a stabilization period of less than 1 second (<1 s), preferably less than 0.5 seconds (<0.5 s), preferably less than 0.25 seconds (<0.25 s), preferably less than 0.1 seconds (<0.1 s), preferably less than 0.05 seconds (<0.05 s), preferably less than 0.03 seconds (<0.03 s), preferably less than 0.02 seconds (<0.02 s), preferably less than 0.01 seconds (<0.01 s).

[0074] In one aspect, the nebulizer provides control over the volumetric spray rate of the nebulized liquid. In particular, the volumetric spray rate of the nebulized liquid can be optimized for a given active agent. In one embodiment, the nebulizer provides a volumetric spray rate of the nebulized liquid in the range of 0.1 to 10 mL / min, preferably in the range of 0.15 to 7.5 mL / min, preferably in the range of 0.2 to 5 mL / min. In one embodiment, the nebulizer provides a volumetric spray rate of the nebulized liquid greater than 0.1 mL / min (>0.1 mL / min), preferably greater than 0.25 mL / min (>0.25 mL / min), preferably greater than 0.3 mL / min (>0.3 mL / min), preferably greater than 0.35 mL / min (>0.35 mL / min), preferably greater than 0.4 mL / min (>0.4 mL / min), preferably greater than 0.45 mL / min (>0.4 mL / min). The present invention provides a nebulized liquid having a flow rate of 5 mL / min, preferably greater than 0.5 mL / min (>0.5 mL / min), preferably greater than 0.55 mL / min (>0.55 mL / min), preferably greater than 0.6 mL / min (>0.6 mL / min), preferably greater than 0.65 mL / min (>0.65 mL / min), preferably greater than 0.7 mL / min (>0.7 mL / min), preferably greater than 0.75 mL / min (>0.75 mL / min).

[0075] In one aspect, the nebulizer described above provides control of the percentage of API administered in the nebulized liquid. In particular, the percentage of API administered may depend on the physicochemical properties of a given active, but can be optimized for a given active agent using the system described above. In one embodiment, the nebulizer described above provides a nebulized liquid in which the percentage of API administered is greater than 60% (>60%), preferably greater than 65% (>65%), preferably greater than 70% (>70%), preferably greater than 75% (>75%), preferably greater than 80% (>80%), preferably greater than 85% (>85%), preferably greater than 90% (>90%), preferably greater than 95% (>95%), preferably greater than 97% (>97%), preferably greater than 98% (>98%), preferably greater than 99% (>99%).

[0076] In one aspect, the nebulizer described above provides control of the trajectory loss in the nebulized liquid. In particular, the trajectory loss can be optimized for a given active agent. In one embodiment, the nebulizer described above provides a nebulized liquid with less than 20% trajectory loss (<20%), preferably less than 15% trajectory loss (<15%), preferably less than 10% trajectory loss (<10%), preferably less than 9% trajectory loss (<9%), preferably less than 8% trajectory loss (<8%), preferably less than 7% trajectory loss (<7%), preferably less than 6% trajectory loss (<6%), preferably less than 5% trajectory loss (<5%).

[0077] In one embodiment, the above-mentioned nebulizer provides control of the fine particle fraction of the nebulized liquid. Fine particle fraction is generally understood as a measure of the mass deposited in the lung during inhalation of approximately isotonic nebulized aerosol. The amount of aerosol inhaled with different fine particle definitions is compared to the amount of aerosol deposited in the lung and alveolar region of approximately isotonic nebulized aerosol. It is recognized that droplet stage 1-7 has 65% of the drug in a form that accumulates or targets deep lung tissue. Fine particle fraction may depend on the physicochemical properties of a given active agent, but can be optimized for a given active agent using the above-mentioned system. In one embodiment, the nebulizer described above provides a fine particle fraction in droplet stages 1-7 of greater than 20% (>20%), preferably greater than 30% (>30%), preferably greater than 35% (>35%), preferably greater than 40% (>40%), preferably greater than 45% (>45%), preferably greater than 50% (>50%), preferably greater than 55% (>55%), preferably greater than 60% (>60%), preferably greater than 65% (>65%), preferably greater than 70% (>70%), preferably greater than 75% (>75%).

[0078] In addition to the above-mentioned active agents, the above-mentioned nebulizer is suitable for nebulizing fluids or samples containing delicate molecules and particles (e.g., DNA, RNAi, peptides, proteins and cells) without denaturing them and maintaining a high nebulization rate (typically more than 1 ml per minute) from start to finish. Previous prior art nebulizers have been limited to 0.1-0.4 ml per minute, which requires long inhalation times, typically several tens of minutes to an hour. Thus, the practical uptake of conventional nebulizers has been limited. The large nebulization rate achievable by the nebulizer of the present invention can significantly shorten administration times.

[0079] The nebulizer of the present invention is a technetium-99mDTPA aerosol ([ 99mThe nebulizer system described above is currently the subject of human clinical trials to determine the efficiency of delivery of active agents to the lungs by inhalation using a nebulizer system (Tc]DTPA aerosol). Initial results indicate that the nebulizer system described above provides effective delivery of nebulized active agents to target tissues.

[0080] [Table 1]

[0081] Variations and modifications that may be deemed obvious to a person skilled in the art are included within the scope of the invention as claimed in the accompanying claims.

Claims

1. Housing and at least one piezoelectric substrate contained within the housing, the piezoelectric substrate having a transducer surface on which at least one electro-acoustic transducer is disposed for generating acoustic energy within the substrate, and an opposing non-transducer surface; a liquid supply system for supplying liquid to at least one of the transducer surface and the non-transducer surface; A nebulizer for spraying liquid droplets, comprising: the liquid supply system including a container for containing the liquid and at least one rigid supply conduit for contacting the substrate and supplying the liquid from the container to the substrate; the liquid supply system is configured to provide a supply of liquid to the substrate such that the supply of liquid to the substrate is regulated by acoustic energy generated within the substrate that draws liquid from the liquid supply system, and does not include a wick in contact with the substrate; Nebulizer.

2. The supply conduit is in the form of a point or needle.

2. The nebulizer of claim 1.

3. the supply conduit being formed from an acoustically reflective material; 3. The nebulizer of claim 1 or 2.

4. The liquid is gravity fed from the container through the supply conduit. A nebulizer according to any one of claims 1 to 3.

5. The liquid is transferred from the container via an active pump system. A nebulizer according to any one of claims 1 to 4.

6. The active pump system is a syringe or a peristaltic pump. The nebulizer of claim 5.

7. the liquid supply system further comprising a flow regulator for providing a steady flow of liquid from the system; A nebulizer as claimed in any one of claims 1 to 6.

8. The flow regulator includes a liquid outlet passage through which liquid can pass, and an air inlet passage connected to the container.

8. The nebulizer of claim 7.

9. an internal chamber connected to the flow regulator; the internal chamber has a peripheral opening into which a peripheral tip of the supply conduit is received; liquid is able to pass between said peripheral opening and said peripheral tip of said supply conduit by capillary action; 9. The nebulizer of claim 8.

10. the substrate is supported on a displaceable mount to control contact of the substrate with the supply conduit; A nebulizer according to any one of claims 1 to 9.

11. The mount includes a pivot support provided at one end thereof and an opposing end supported by an elastic member.

11. The nebulizer of claim 10.

12. The mount is supported by a cantilever.

11. The nebulizer of claim 10.

13. Further comprising a control means for controlling the size of the atomized droplets. A nebulizer according to any one of claims 1 to 12.

14. the control means including at least one baffle disposed in substantially parallel adjacent relationship with at least one of the transducer surfaces; 14. The nebulizer of claim 13.

15. the baffle being provided by an inner housing wall disposed in parallel adjacent relationship from at least one of the substrate surfaces; 15. The nebulizer of claim 14.

16. The housing further includes an inlet opening. the container includes a neck receivable within the inlet opening; 16. A nebulizer according to any one of claims 1 to 15.

17. at least two of said substrates disposed in spaced apart parallel adjacent relationship; 17. A nebulizer according to any one of claims 1 to 16.

18. the droplet size control means includes controlling a size of the sprayed droplets by presetting a spacing between the substrates to control a thickness of a meniscus of the liquid supplied between adjacent substrate surfaces; 18. The nebulizer of claim 17.

19. the droplet size control means includes controlling the size of the atomized droplets by presetting a spacing of the substrate from an inner wall of the housing to control a thickness of a meniscus of the liquid dispensed between adjacent substrate surfaces.

19. A nebulizer as described in claim 17 or claim 18.

20. The piezoelectric substrate and electroacoustic transducer are also used to sense a liquid mass on the at least one substrate.

20. A nebulizer according to any one of claims 1 to 19.

21. Housing and at least one piezoelectric substrate contained within the housing, the piezoelectric substrate having a transducer surface on which at least one electro-acoustic transducer is disposed for generating acoustic energy within the substrate, and an opposing non-transducer surface; a compliant material in contact with at least a portion of the outer circumferential surface of the at least one piezoelectric substrate; a liquid supply system for supplying liquid to at least one of the transducer surface and the non-transducer surface; A nebulizer for spraying liquid droplets, comprising: the liquid supply system comprising a container for containing the liquid and at least one supply conduit for supplying the liquid from the container to the substrate; the liquid supply system is configured to provide a supply of liquid to the substrate such that the supply of liquid to the substrate is regulated by acoustic energy generated within the substrate that draws liquid from the liquid supply system, and does not include a wick in contact with the substrate; Nebulizer.

22. the flexible material is selected from the group consisting of adhesive tape, silicone rubber, and thermal paste, or a combination thereof; 22. The nebulizer of claim 21.

23. the compliant material contacts at least a portion of the periphery of the distal end of the substrate.

23. A nebulizer as described in claim 21 or 22.

24. the at least one supply conduit is a relatively rigid supply conduit in contact with the substrate; 24. A nebulizer according to any one of claims 21 to 23.

25. The at least one supply conduit is selected from the group consisting of a tip, a needle, a wick, a microchannel, or a combination thereof; 24. A nebulizer according to any one of claims 21 to 23.

26. At least a portion of the transducer surface, the non-transducer surface, or a combination thereof, is patterned.

26. A nebulizer according to any one of claims 1 to 25.

27. the acoustic energy includes surface acoustic waves (SAW) propagating on the transducer surface of the at least one substrate; 27. A nebulizer according to any one of claims 1 to 26.

28. the sonic energy includes surface reflected bulk waves (SRBW) that reflect between the transducer surface and the non-transducer surface of the at least one substrate; 28. A nebulizer according to any one of claims 1 to 27.

29. the acoustic energy includes a combination of surface acoustic waves (SAW) propagating at the transducer surface of the at least one substrate and surface reflected bulk waves (SRBW) reflecting between the transducer surface and the non-transducer surface of the at least one substrate; 29. A nebulizer according to any one of claims 1 to 28.

30. The surface acoustic wave (SAW) includes a standing wave, a traveling wave, and a combination thereof.

30. A nebulizer according to any one of claims 27 or 29.

31. The surface reflected bulk wave (SRBW) includes a standing wave, a traveling wave, and a combination thereof.

30. A nebulizer according to any one of claims 28 or 29.

32. The electroacoustic transducer is an interdigital transducer (IDT).

32. A nebulizer according to any one of claims 1 to 31.

33. the at least one piezoelectric substrate has a thickness that is at or near the wavelength of the SAW propagating on the transducer surface; 33. A nebulizer according to any one of claims 1 to 32.

34. The at least one piezoelectric substrate is formed from lithium niobate (LiNbO3).

34. A nebulizer according to any one of claims 1 to 33.

35. at least a portion of the non-transducer surface further comprises a coating comprised of at least one metal; 35. A nebulizer according to any one of claims 1 to 34.

36. at least a portion of the transducer surface further comprises a coating comprised of at least one metal at the distal end of the substrate; 36. A nebulizer according to any one of claims 1 to 35.

37. The coating is comprised of titanium, gold, aluminum, chromium, or a combination thereof.

37. A nebulizer as described in claim 35 or claim 36.

38. the liquid is sprayed from the transducer surface, the non-transducer surface, or from both the transducer surface and the non-transducer surface; 38. A nebulizer according to any one of claims 1 to 37.

39. The liquid is atomized to form droplets having a size in the range of 0.1 to 100 μm.

39. A nebulizer according to any one of claims 1 to 38.

40. The liquid is sprayed at a spray rate of up to 10 ml / min.

40. A nebulizer according to any one of claims 1 to 39.

41. the mount includes a shelf on which the substrate rests; the shelf includes one or more gaps to prevent liquid creep along the substrate. A nebulizer according to any one of claims 10 to 12.

42. the housing being in the form of a cartridge housing having external electrical contacts connected to the at least one electro-acoustic transducer and an integral liquid supply system; 42. A nebulizer according to any one of claims 1 to 41.

43. 43. A method of nebulizing a liquid using a nebulizer according to any one of claims 1 to 42.

44. 44. A method of atomizing a liquid according to claim 43, comprising the step of atomizing the liquid to form droplets having a size in the range of 0.1 to 100 μm.

45. spraying the liquid at a volumetric spray rate of up to 10 ml / min; 44. A method for atomizing a liquid according to claim 43.

46. Atomizing a liquid to form droplets having a geometric standard deviation (GSD) of less than 10 μm (<10 μm); 44. A method for atomizing a liquid according to claim 43.

47. The liquid contains functional or therapeutic substances such as pharmaceuticals, DNA, RNAi, peptides, proteins and cells, or non-therapeutic substances such as fragrances, cosmetics, insecticides, paints or preservatives; 47. A method for atomizing a liquid according to any one of claims 43 to 46.

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