Devices, systems, and methods of using the devices and systems

Abstract

The present disclosure provides for devices, systems, and methods for flowing a fluid. The fluid can include cells and other agents that can interact with the cells during processing of the cells. In an aspect, the present disclosure provides for devices, systems and methods that use a control system with a feedback loop to modify the flow of the fluid as one or more variables change during operation of the device, system, or method.

Description

[0001] DEVICES, SYSTEMS, AND METHODS OF USING THE DEVICES AND SYSTEMS

[0002] CLAIM OF PRIORITY TO RELATED APPLICATION

[0003] This application claims priority to U.S. provisional application entitled “DEVICES AND METHODS OF USING THE DEVICE” having Serial No.: 63 / 519,997, filed on August 16, 2023, which is entirely incorporated herein by reference.

[0004] BACKGROUND

[0005] Controlling fluid flow in a system that includes cells can be challenging. Despite efforts to address this challenge, current techniques are not as effective as desired, and there is a need to address various deficiencies.

[0006] SUMMARY

[0007] Embodiments of the present disclosure provide for devices, systems, and methods for flowing a fluid.

[0008] In an aspect, the present disclosure provides for a system, comprising: a fluid reservoir configured to hold a fluid, wherein the fluid reservoir includes a nozzle array ejector on a first side of the fluid reservoir and the nozzle array ejector is in fluidic communication with the fluid, wherein the fluid reservoir is configured to receive fluid from a fluid feed system; and an actuator holder, wherein the actuator holder includes a transducer stack on a first side of the actuator holder, wherein the actuator holder fits within the fluid reservoir, wherein at least a part of the actuator holder is within the fluid, wherein the first side of the actuator holder is within the fluid and at least one other area of the actuator holder is within the fluid; wherein the fluid is driven from the fluid reservoir through the nozzle array ejector upon actuation of the transducer stack to generate a mechanical wave, an acoustic wave, or both within the fluid reservoir and actuator holder, wherein the acoustic wave, the mechanical wave, or both cause the flow of fluid through the nozzle array ejector, a control system is configured to control the flow of the fluid through the nozzle array ejector using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a temperature of the fluid, the fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a pressure within the fluid reservoir, a fluid flow into the fluid reservoir from the fluid feed system, a gap distance from the fluid reservoir to the actuator holder, an optical image of the fluid volume and fluid through the nozzle array ejector, or an ultrasound transmission through the ejected fluid through the nozzle array ejector. In an aspect, the present disclosure provides for a method of controlling the flow of a fluid, comprising: filling a fluid reservoir with a fluid, wherein the fluid reservoir includes a nozzle array ejector on a first side of the fluid reservoir and the nozzle array ejector is in fluidic communication with the fluid, wherein an actuator holder is within the fluid reservoir, wherein the actuator holder includes a transducer stack on a first side of the actuator holder, wherein the first side of the actuator holder is within the fluid and at least one other area of the actuator holder is within the fluid, driving a transducer stack, wherein the transducer stack produces an acoustic wave, a mechanical wave, or both, and flowing the fluid through a nozzle array ejector a flow rate in response to driving the transducer stack, wherein flowing the fluid through the nozzle array ejector is controlled using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a temperature of the fluid, a fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a pressure within the fluid reservoir, a fluid flow into the fluid reservoir from the fluid feed system, a gap distance from the nozzle array ejector to the actuator holder, an optical image of the fluid volume and fluid through the nozzle array ejector, or an ultrasound transmission through the flowed fluid through the nozzle array ejector, wherein when one or more of the variable changes, then the flow rate of the fluid through the nozzle array ejector is adjusted, the fluid flow into the fluid reservoir is adjusted, or both are adjusted.

[0009] Other systems, devices, methods, features, and advantages will be, or become, apparent to one with skill in the art upon examination of the following drawings and detailed descriptions. It is intended that all such additional compositions, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims.

[0010] BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Many aspects of this disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure.

[0012] Fig. 1 illustrates a block diagram of an aspect of the present disclosure.

[0013] Figs. 2A-2C illustrate a cross-sectional diagram of an aspect of the present disclosure, where the left side of Fig. 2C illustrates a simulation of a bending mode of the actuator holder.

[0014] Fig. 3 illustrates a cross-sectional diagram of an aspect of the present disclosure

[0015] Fig. 4 is a graph that illustrates variation of electrical impedance magnitude of the actuator with frequency for three different fluid volume levels in the fluid reservoir. Fig. 5 illustrates a cross-sectional diagram of an aspect of the present disclosure

[0016] Fig. 6 illustrates an embodiment of the nozzle array ejector.

[0017] Fig. 7 illustrates a flow chart of an embodiment of the method of operation of the device or system of the present disclosure.

[0018] Fig. 8 illustrates a flow chart of an embodiment of the method of operation of the device or system of the present disclosure.

[0019] DETAILED DESCRIPTION

[0020] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0021] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit (unless the context clearly dictates otherwise), between the upper and lower limit of that range, and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

[0023] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

[0024] Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of engineering, chemistry, biochemistry, biology, molecular biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods and use the compositions and compounds disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight and temperature is in °C. Standard temperature and pressure are defined as 20 °C and 1 atmosphere.

[0025] Before the embodiments of the present disclosure are described in detail, it is to be understood that, unless otherwise indicated, the present disclosure is not limited to particular materials, reagents, reaction materials, manufacturing processes, or the like, as such can vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It is also possible in the present disclosure that steps can be executed in different sequence where this is logically possible.

[0026] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a support” includes a plurality of supports. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

[0027] Discussion:

[0028] Embodiments of the present disclosure provide for devices, systems and methods for flowing a fluid. The fluid can include cells and other agents that can interact with the cells during processing of the cells. In an aspect, the present disclosure provides for devices, systems and methods that use a control system with a feedback loop to modify the flow of the fluid as one or more variables change during operation of the device, system or method.

[0029] Earlier systems for payload delivery to cells considered a fixed geometry for the actuator, reservoir, nozzles and fluidic domain and assumed static conditions during device operation. While that assumption is suitable for small sample volumes and batch operation over a short time, many applications of molecular delivery to cells require larger volumes, higher flow rates and high throughput. As a result, the system operation should be responsive and adapt to dynamic changes that can occur in the system startup and in the longer time frame for sustained continuous or semi-continuous operation with other fluidic components such as pumps. These changes include, but are not limited to, transducer stack temperature, pressure in the fluid reservoir, change in fluid volume and temperature, other dimensional changes due to thermal expansion of the system, change in condensation of droplets impacting flow (e.g., ejection) from a nozzle array ejector, and the like. Embodiments of the present disclosure describe improved devices, systems and methods to enable sustained and automated operation of fluid flow from the nozzle array ejector to achieve based molecular delivery to cells.

[0030] In an aspect, the devices, systems and methods of the present disclosure use a control system based on one or more sensors that provide feedback information for sustained continuous or semi-continuous operation. In addition, the systems and methods can use structures to reduce the variations in some of the variables that can impact system performance.

[0031] In an aspect, the devices, systems and methods can flow a fluid out of the device or system by operating at a frequency that corresponds to a mechanical resonant mode of the entire system or device structure. Therefore, the efficiency of the device or system and the fluid flow output can be impacted by geometrical or material variables or parameters that can change the resonance frequency of the system or device structure. The sensitivity of resonance to different variables and parameters can also depend upon the mode shape and energy distribution (e.g., acoustic and / or mechanical waves that drive the flow of the fluid out of the device or system).

[0032] The fluid in the fluid reservoir can include liquids such as, but not limited to, water, methanol, dielectric fluorocarbon fluid, organic solvent, cell culture media, buffer solutions, electroporation buffers, or other liquids, and combinations thereof. Fluid samples can also include suspensions of biological cells and / or one or more other materials, including but not limited to, drug molecules, nucleic acids, imaging agents, peptides, antibodies, enzymes, and other nanomaterials and biomolecules.

[0033] If the fluid sample contains biological cells, ejection from the orifices of the ejection device (e.g., flow through the nozzle array ejector) can provide a mechanical shear force that induces a tension in the cell membranes. Provided the induced membrane tension exceeds a certain threshold value, cells can be either reversibly porated for cargo molecule delivery or irreversibly porated leading to eventual cell death or immediate cell lysis.

[0034] In a non-limiting example and for purposes of illustration, the transducer stack can include a piezoelectric or capacitive transducer and an acoustic coupling structure, each of which can be used in thickness expansion mode. In this mode, the acoustic energy is confined mostly in the fluid layer between the coupling surface and the nozzle array ejector. Then the gap between the coupling structure and the nozzle array ejector and the thickness of the transducer and coupler layer are parameters that can affect the flow of the fluid through the nozzle array ejector, whereas the total fluid volume in the reservoir outside the fluid layer may have less impact upon the flow of the fluid. In another non-limiting example, the transducer stack comprises an active layer and passive layer (acoustic coupling structure) can be used in a bending vibration mode or operate substantially in an out of plane bending mode (e.g., a bimorph or unimorph structure) in the about 10 kHz to 400 kHz range where the energy in the system can extend to the whole ejector structure and the fluid reservoir. This can be achieved by restraining the lateral expansion of the passive layer by placing it in a structure that is rigid at the lateral edges. In this bending vibration mode, the transducer stack can move in vertical direction by bending but the passive layer can only minimally (e.g., about 5% or less, about 3% or less, about 1% or less) expand laterally (Fig. 2C). In this embodiment, the system or device operation and resonance frequency can be more sensitive to overall fluid reservoir dimensions and the total volume of the fluid in the fluid reservoir.

[0035] In general, these different modes of operation may require different types of variables to be sensed and modified to achieve the desired flow of the fluid through the nozzle array ejectors. For example, in the thickness resonance mode the fluid filled gap thickness between nozzle array ejectors and the actuator holder can be impactful while in the bending vibrational mode the overall fluid volume in the fluid reservoir can be impactful.

[0036] Now having described embodiments of the present disclosure in general, additional details will be provided below. Aspects of the present disclosure include devices, systems and methods that use a feedback system to control the fluid flow out a nozzle array ejector of a fluid reservoir. As shown in Fig. 1, a system 10 (or a device) can include a fluid reservoir 12, where an actuator holder 14 is within the fluid reservoir 12. A control system 16 is in communication (e.g., direct and / or indirect) with the fluid reservoir 12 (or component therein) and the actuator holder 14 (or components therein). The control system 16 can measure one or more variables, control (directly and / or indirectly) one or more variables, and provide a feedback loop so that the fluid flow out of the nozzle array ejector is within a desired flow rate (e.g., about 1 ml / min to 1000 ml / min, about 1 ml / min to 500 ml / min, or about 1 ml / min to 200 ml / min) depending on the number of nozzles (e.g., about 1 ml / min to 200 ml / min for a nozzle array with about 300 nozzles).

[0037] Fig. 2A illustrates a portion of the system 10 (the control system 16 is not illustrated). The actuator holder 14 is within the fluid 26 of the fluid reservoir 12. The actuator holder 14 includes a transducer stack 24. The fluid reservoir 12 includes a nozzle array ejector 22. While Fig. 2A illustrates that the transducer stack 24 is positioned at the bottom of the actuator holder 14 and adjacent the nozzle array ejector 22, the transducer stack 24 can be positioned on another area or side of the actuator holder 14. The actuator holder 14 is illustrated as having an opening on the top side of the actuator holder 14, the actuator holder 14 may not have an opening on the top side. A fluid flow system (not shown) can be used to flow fluid into the fluid reservoir 12. As the fluid 26 is flowed (e.g., ejected) through the nozzle array ejector 22, the volume of the fluid 26 in the fluid reservoir 12 can decrease. The control system 16 can be used to control the flow of the fluid 26 into the fluid reservoir 12 and control the flow rate of the fluid 26 through the nozzle array ejector 22.

[0038] Fig. 2B illustrates an embodiment of the system 10 that illustrates the control system 16 that can control the fluid 26 flow into the fluid reservoir 12, interface, measure, and control variables such as, but not limited to, fluid level (or fluid volume in the fluid reservoir), temperature of the fluid 26 in the fluid reservoir 12, temperature of the fluid 26 as it is flowed through the nozzle array ejector 22, pressure in the fluid reservoir 12, flow rate of the fluid 12 through the nozzle array ejector 22, frequency applied to the actuator, as well as other variables that will be described herein.

[0039] Figs. 1, 2A, and 2B illustrates various features of the present disclosure and the following will provide a description and discussion of the devices, systems and methods of the present disclosure.

[0040] In an aspect, the present disclosure provides a system that includes a fluid reservoir, an actuator holder and a control system. The fluid reservoir is configured to hold a fluid. The fluid can be flowed into the fluid reservoir using a fluid feed system. The fluid reservoir includes a nozzle array ejector on a first side of the fluid reservoir. In an aspect, the nozzle array ejector is positioned on the bottom of the fluid reservoir, but the nozzle array ejector could be positioned elsewhere (e.g., on a side or top) in the fluid reservoir in some embodiments. The nozzle array ejector is in fluidic communication with the fluid and can flow (e.g., eject) the fluid out of the fluid reservoir. In an aspect, the flow of the fluid through the nozzle array ejector can be continuous or quasi-continuous. The control system can be used to control the continuous or quasi-continuous flow of the fluid through the nozzle array based on the feedback loop of various variables.

[0041] The fluid reservoir can be made of materials such as plastics, metals (e.g., aluminum, steel, and / or brass), and glass. The dimensions of the fluid reservoir can be about 100 micrometers to 20 centimeters in width, about 100 micrometers to 20 centimeters in length, and about 1 micrometer to 10 centimeters in height. The fluid reservoir can include about 1 microliter to 1 milliliter or 1 milliliter to 1000 milliliter of fluid. The fluid reservoir can receive fluid from a fluid feed system that includes tubing, valves, flow controllers, a larger external reservoir, a pump and the like to control the flow of the fluid into the fluid reservoir. The control system is in communication with various components such as the fluid feed system so that the fluid flow into the fluid reservoir can be controlled.

[0042] In an aspect, the fluid reservoir can include a cap structure to limit the total volume of the fluid. Fig. 5 illustrates a cap structure 42. This cap structure has low rigidity so that the coupling of vibrations from the actuator holder to the reservoir walls is minimized while the cap structure does not impact the acoustic and mechanical waves in the system. One possible embodiment of the cap can use a thin (e.g., about 1 micrometer to 200 micrometer) elastomer membrane. The thickness of this structure is substantially (e.g., about 0.01x) larger than any vibration wavelength and its mass is small so that the vibration of the fluid surface is not impacted, i.e. the fluid surface moves like a free surface as if the cap is not there. Therefore, this cap keeps the fluid volume constant while not impacting the overall mechanical behavior of the system as compared to a system with free surface.

[0043] In general, the material from which the nozzle array ejector is made can have a substantially higher acoustic impedance as compared to the fluid sample. The nozzle array ejector can be made of materials such as, but not limited to, single crystal silicon (e.g., oriented in the (100), (010), or (001) direction), metals (e.g., aluminum, copper, and / or brass), plastics, silicon oxide, silicon nitride, and combinations thereof. Fig. 6 illustrates an embodiment of the nozzle array ejector.

[0044] The nozzle array ejector can have a shape such as, but not limited to, conical, pyramidal, or horn-shaped with different cross-sections. In general, the cross-sectional area is decreasing (e.g., linear, exponential, or some other functional form) from a base of the nozzle array ejector (broadest point adjacent the reservoir) to the ejector orifice in both two and three dimensions. The cross sections can include, but are not limited to, a triangular cross-section and exponentially narrowing. In an embodiment, the nozzle array ejector can be a pyramidal shape. In an embodiment, the nozzle array ejector can be a two-dimensional groove terminated by a slot orifice or have a three-dimensional tapered geometry terminated by an arbitrarily-shaped orifice (e.g., circle, square, etc., see below). In another embodiment, geometry of the nozzle array ejector is not tapered, but is terminated by an opening / channel orifice, which is of substantially smaller dimension (width or diameter) than the nozzle array ejector.

[0045] In one embodiment, the nozzle array ejector has acoustic wave focusing properties in order to establish a highly-localized, pressure maximum substantially close to the ejector orifice. This results in a large pressure gradient at the ejector orifice since there is effectively an acoustic pressure release surface at the ejector orifice. Since the acoustic velocity is related to the pressure gradient through Euler’s relation, a significant momentum is transferred to the fluid sample volume close to the ejector orifice during each cycle of the acoustic wave in the nozzle array ejector. When the energy coupled by the acoustic wave in the fluid sample volume is substantially larger than the restoring energy due to surface tension, viscous friction, and other sources, the fluid surface is raised from its equilibrium position. Furthermore, the frequency of the waves can be such that there is enough time for the droplet to break away from the surface due to instabilities. Alternatively, the frequency of the waves can be such that the ejection is an unbroken jet of the fluid.

[0046] The nozzle array ejector can have a diameter (at the base of a single structure / nozzle) of about 50 micrometers to 5 millimeters, 300 micrometers to 1 millimeter, and 600 micrometers to 900 micrometers. The distance (height) from the ejector orifice

[0034] (opening) to the broadest point in the nozzle array ejector (base of the nozzle) is from about 20 micrometers to 4 millimeters, 200 micrometers to 1 millimeter, and 400 micrometers to 600 micrometers.

[0047] The nozzle array ejector size and shape effectively determine the droplet / jet size and the amount of pressure focusing along with the nozzle array ejector geometry (i.e. , cavity geometry). The ejector orifice can be formed using various manufacturing techniques as described below and can have a shape such as, but not limited to, circular, polygonal, elliptical, square, rectangle, or rhomboid. The ejector orifice can have a diameter of about 50 nanometers to 200 micrometers, 200 nanometers to 100 micrometers, and 1 micrometer to 10 micrometers.

[0048] The nozzle array ejector can include one nozzle array ejector, an (one-dimensional) array of nozzle array ejector, or a (two dimensional) matrix of parallel arrays of nozzle array ejector. The nozzle array ejector can include one nozzle array ejector each or include a plurality of ejector orifices in a single ejector structure.

[0049] In an aspect, the fluid reservoir includes a droplet accumulation device to limit droplet accumulation on the nozzle array ejector. For example, the droplet accumulation device has the characteristic of producing a pressure differential (e.g., air flow or vacuum) across the nozzle array ejector to limit or eliminate droplet accumulation. Fig. 6 illustrates an embodiment of the device to limit droplet accumulation on the nozzle array ejector.

[0050] As described above, the device or system can include an actuator holder. The actuator holder includes a transducer stack. The transducer stack includes an actuator and an acoustic coupler. In an aspect, the transducer stack can be positioned on a first side of the actuator holder, for example on a bottom side of the actuator holder and adjacent the nozzle array ejector. The actuator holder has dimensions so that it fits within the fluid reservoir. At least part of the actuator holder is within the fluid. For example, the first side of the actuator holder (where the transducer stack is positioned) is within the fluid and at least one other area of the actuator holder is within the fluid. In an aspect, the actuator holder is within the fluid of the fluid reservoir so that acoustic or mechanical energy (e.g., an acoustic wave and / or mechanical wave) can cause the fluid to flow through the nozzle array ejector. In particular, the fluid can be driven from the fluid reservoir through the nozzle array ejector upon actuation of the transducer stack to generate a mechanical wave, an acoustic wave, or both within the fluid reservoir and actuator holder.

[0051] The actuator holder can be made of materials such as metals (e.g., aluminum, steel, copper, and / or brass) or glass. The dimensions of the actuator holder can be about 1 millimeter to 30 centimeters in width, about 1 millimeter to 30 centimeters in length, and about 1 millimeter to 40 centimeters in height.

[0052] The control system is in communication with the actuator holder, in particular, the control system is in communication (electrical communication) with the transducer stack. The control system can cause the actuator of the transducer stack to function to cause the fluid to flow through the nozzle array ejector and can also function as a sensor to measure a driving point electrical impedance magnitude, a driving point electrical impedance phase, or both. The feedback loop of the control system can function to control the flow rate of the fluid through the nozzle array ejector and the flow of the fluid into the fluid reservoir using the fluid flow system.

[0053] The transducer stack can produce an acoustic and / or mechanical wave (e.g., resonant acoustic or mechanical wave) within the fluid reservoir and fluid volume. In an embodiment, the acoustic wave (e.g. resonant acoustic wave) couples to and transmits through the fluid and can be focused by the nozzle array ejector to form a pressure gradient within the ejector structure to flow (e.g., eject) the fluid through the orifices of the nozzle array ejector. If the orifices are open for ejection, a high-pressure gradient accelerates fluid out of the orifices from the ejector structure to produce ejection of the fluid (e.g., fluid flow or flow rate of the fluid). Ejection can produce discrete droplets in a continuous jet or semi- continuous jet for continuous fluid flow or semi-continuous fluid flow. In an embodiment, the frequency at which the droplets are formed is a function of the drive wave form applied to the transducer stack as well as the fluid, fluid reservoir, nozzle array ejector structure, the ejector orifice, and the like.

[0054] The transducer stack can include an actuator and acoustic coupler structure. Different actuators can be used to flow the fluid, including the piezoelectric and capacitive type (e.g., CMLIT) actuators. An alternating voltage can be applied to the actuator to cause the actuator to produce the acoustic wave. During actuator operation at the electrical drive voltage amplitude is about 1 V to 1000 V, the electrical drive current amplitude is about 0.01 A to 5 A, the electrical drive duty cycle for burst operation is about 1% to 99%, the electrical drive signal frequency is about 1 kHz to 10 MHz. A direct current (DC) bias voltage can also be applied to the actuator in addition to the alternating voltage. In embodiments where the actuator is piezoelectric, this bias voltage can be used to prevent depolarization of the actuator and also to generate an optimum ambient pressure in the fluid reservoir. In embodiments where the actuator is electrostatic, the bias voltage is needed for efficient and linear operation of the actuator. Operation of the actuator can be optimized within these frequency ranges in order to match the resonances of various components (e.g., fluid reservoir, nozzle array ejector, and the like) and the overall system as a whole, and depends on the dimensions of and the materials used for fabrication of the fluid reservoir, actuator holder and the nozzle array ejector as well the acoustic properties of the fluid sample.

[0055] The actuator can include, but is not limited to, a piezoelectric actuator and a capacitive actuator. The piezoelectric actuator and the capacitive actuator are described in X.C. Jin, I. Ladabaum, F.L. Degertekin, S. Calmes and B.T. Khuri-Yakub, “Fabrication and Characterization of Surface Micromachined Capacitive Ultrasonic Immersion Transducers”, I EEE / ASME Journal of Microelectromechanical Systems, 8, pp. 100-114 (1999) and Meacham, J. M., Ejimofor, C., Kumar, S., Degertekin F. L., and Fedorov, A., “A Micromachined Ultrasonic Droplet Generator Based on Liquid Horn Structure”, Rev. Sci. Instrum., 75 (5), 1347-1352 (2004), which are incorporated herein by reference.

[0056] The actuator can also be used in bending (bimorph or unimorph) mode using a piezoelectric transducer bonded to a passive layer with constrained lateral motion as described in Herz, Markus, David Horsch, Gerhard Wachutka, Tim C. Lueth, and Martin Richter. "Design of ideal circular bending actuators for high performance micropumps." Sensors and Actuators A: Physical 163, no. 1 (2010): 231-239 (which is incorporated herein by reference).

[0057] In this mode of operation, the piezoelectric transducer’s lateral dimensions are smaller than the inner later dimensions of the actuator holder, so that while the piezoelectric transducer can expand laterally, the acoustic coupler region of the actuator holder expands much less causing the structure to bend. When a single piezoelectric layer is used as the active layer and an acoustic coupler layer is used as the passive layer, the configuration is called a unimorph, if the coupling layer is sandwiched between two piezoelectrics, it is called a bimorph. For most cases considered here, using a single piezoelectric layer over the acoustic coupler layer is preferred for bending mode operation. The material for the passive layer can be the same material as the actuator holder or can be separate, but the suitable materials are high stiffness and low acoustic loss materials such as metals (e.g., aluminum, steel, copper, and / or brass) or glass.

[0058] The dimensions of the actuator depend on the type of actuator used. For embodiments where the actuator is a piezoelectric actuator and it is used in the thickness expansion mode, the thickness of the actuator is determined, at least in part, by the frequency of operation and the type of the piezoelectric material. The thickness of the piezoelectric actuator is chosen such that the thickness of the actuator is about half the wavelength of longitudinal waves in the piezoelectric material at the frequency of operation. Therefore, in case of a piezoelectric actuator, the dimensions of the actuator are about 100 micrometers to 1 centimeter in width, about 10 micrometers to 2 millimeters in thickness, and about 100 micrometers to 1 centimeter in length.

[0059] When the actuator is used in the bending mode, the dimensions are determined at least in part, by the frequency of operation and the type of the piezoelectric material and the acoustic coupler layer material (which can be the same as the actuator holder material). The lateral dimensions are chosen such that the operation frequency is close to a bending mode resonance of the transducer stack considering the lateral dimensions of the actuator holder which is constraining the lateral motion of the acoustic coupling portion of the actuator holder. Therefore, in bending mode operation, a piezoelectric actuator can be about 1 millimeter to 30 centimeters in width, about 1 millimeter to 30 centimeters in length (for a circular actuator the diameter can be about 1 millimeter to 30 centimeters) and 10 micrometers to 10 millimeters in thickness. For bending mode, the acoustic coupler layer is larger in width and length than the piezoelectric actuator and can be 10 micrometers to 20 millimeters in thickness.

[0060] In embodiments where the actuator is a capacitive actuator, the actuator is built on a wafer made of silicon, glass, quartz, or other substrates suitable for microfabrication, where these substrates determine the overall thickness of the actuator. Therefore, in case of a capacitive microfabricated ultrasonic transducer (CMLIT) and CMLIT arrays, the dimensions of the actuator are about 10 micrometers to 4 centimeters in width, about 10 micrometers to 2 millimeter in thickness, and about 10 micrometers to 4 centimeters in length.

[0061] In an aspect, a waveform generator can be in electrical communication with the transducer stack. The waveform generator generates a signal at one or more of the following: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency. The electrical drive voltage amplitude is about 1V to 1000 V, the electrical drive current amplitude is about 0.01 A to 5 A, the electrical drive duty cycle for burst operation is about 1% to 99%, the electrical drive signal frequency is about 1 kHz to 10 MHz. In an aspect, the electrical drive signal frequency is at a frequency that is about a frequency of an electromechanical resonance of the system (e.g., the fluid reservoir, the actuator holder, or both).

[0062] In an aspect, the transducer stack can operate in a thickness expansion mode, where the transducer stack exhibits substantially (e.g., about 90% or more, about 95% or more) thickness expansion motion. In this embodiment, the actuator is a capacitive actuator. The fluid can be flowed through the nozzle array ejector when the transducer operates in this mode. In this mode, the control system can measure the following variables: gap thickness and flow rate out of the nozzles. The control system can use data from these variables to make adjustments to the actuation of the transducer stack to achieve the desired flow rate of the fluid through the nozzle array ejector.

[0063] In an aspect, the transducer stack operates in a bending vibration mode, where the transducer stack operates substantially in an out of plane bending mode. In this embodiment, the actuator is a piezoelectric actuator. In this mode, the actuator holder bends, which produces an acoustic and / or mechanical wave that cause the fluid to flow through the nozzle ejector array. In an aspect, the actuator holder is a substantially rigid structure at the lateral edges, where the transducer stack bends in a vertical direction but expands minimally (e.g., about 10% or less, about 5% or less, about 3% or less) in the lateral direction which causes the rigid structure to bend during operation of the transducer stack (See Fig. 2A, left side).

[0064] In an aspect, when the transduce stack includes an electromechanical actuator, typically a piezoelectric transducer, which generates the mechanical force for ejection, the electromechanical coupling of the transducer allows one to not only drive the fluid flow through the nozzle array ejector but also monitor the mechanical behavior of the system. This is achieved by measuring the driving point electrical impedance of the actuator during operation using an actuator driver circuit. The electromechanical resonances of the system (e.g., fluid reservoir and / or actuator holder) can be identified by maxima and minima in the magnitude of the impedance or transitions in phase of the impedance when plotted as a function of frequency (See Fig. 4). This information is used to decide on the electrical drive signal frequency and amplitude to achieve efficient ejection using a particular mode. Typically, the system is driven close to a minimum of the impedance, around the series resonance frequency, as more power is coupled with lower voltage levels. When a parameter of the system changes, for example the volume of the fluid in the reservoir, the resonance frequency and the overall behavior of the impedance changes. This allows the actuator to be used both as an actuator and sensor through real-time impedance measurement during system operation. Therefore, the magnitude and phase of the impedance can be conveniently used for feedback operation, indirectly providing information on and adapting to the changes in parameters like fluid gap thickness, temperature, fluid volume etc. for robust and continuous system operation.

[0065] In an aspect, the system (e.g., the fluid reservoir and / or the actuator holder) can include one or more of the following sensors: electrical input impedance magnitude and phase sensors and circuits, one or more pressure sensors, one or more temperature sensors, one or more fluid level sensors, one or more flow rate sensors, one or more vibrational sensors, one or more optical or ultrasonic sensors to monitor fluid ejection from the nozzle array.

[0066] While the present disclosure can use various sensors, the approach of using the actuator as a sensor can reduce the required number of different sensors which can directly measure these parameters or can be augmented with other sensors which may directly provide these parameters. For example, it may not be feasible or easy to include a fluid level sensor due to the small volume of the reservoir, but impedance measurement can provide that information.

[0067] While the driving point impedance measurement method is known for feedback in high power ultrasonic devices to keep vibration amplitude constant (Kuang, Y., Jin, Y., Cochran, S. and Huang, Z., 2014. Resonance tracking and vibration stablilization for high power ultrasonic transducers. Ultrasonics, 54(1), pp.187-194), it has not been used in biofluidic systems as described herein and for the delivery of payloads to biological systems.

[0068] Based on the real-time measured electrical impedance of the actuator and sensors, the control system can use this information as a feedback loop to regulate the flow rate of the fluid through the nozzle array ejector and cell shear stress and match the flow input from the fluid feeding system into the fluid reservoir by adjusting the input signal to the acoustic actuator (piezoelectric or capacitive transducer), for example. In an aspect, the adjustments can include voltage amplitude, current amplitude, duty cycle for burst operation, and frequency applied to the transducer stack.

[0069] In addition to being used in the control loop for continuous operation the transducer impedance information can be used to estimate the flow rate from the fluid feeding system into the fluid reservoir through fluid level / volume detection. The quantitative relations between the parameters such as fluid level / volume, temperature, and the transducer impedance can be obtained through calibration for different transducers and reservoir and used during real-time operation of the system.

[0070] In an embodiment where the transducer stack operates in bending mode, the acoustic coupler serves as the passive layer for a unimorph whereas the piezoelectric transducer is the active layer. The acoustic coupler can be a high stiffness and low acoustic loss material such as metals (e.g., aluminum, steel, copper, and / or brass) or glass.

[0071] In an embodiment where the transducer stack operates in thickness expansion mode, the acoustic coupler serves as a propagation medium for waves going through its thickness. In this case, again the acoustic coupler can be a high stiffness and low acoustic loss material such as metals (e.g., aluminum, steel, copper, and / or brass) or glass.

[0072] In an aspect, the actuator holder can include a mechanical actuator. The mechanical actuator is capable of changing the gap height distance 32 (See Fig. 3) from the transducer stack and the nozzle ejector array. In an aspect, the gap distance can be about 1 micrometer to 10 centimeters in height.

[0073] In addition, to the fluid reservoir and the actuator holder, the device or system includes a control system. Some aspects and features of the control system have been described above. Additional aspects and features of the control system are provided below. The control system is configured to control the flow of the fluid through the nozzle array ejector using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a temperature of the fluid (e.g., in the fluid reservoir and / or exiting the nozzle array ejector), the fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a pressure within the fluid reservoir, a fluid flow into the fluid reservoir from the fluid feed system, a gap distance from the fluid reservoir to the actuator holder (e.g., see Fig. 3), an optical image of the fluid volume and fluid through the nozzle array ejector, light transmission through the ejected fluid through the nozzle or an ultrasound transmission through the ejected fluid through the nozzle array ejector. The fluid reservoir and the actuator holder can include a sensor(s) to measure each of the variable. In addition, the control system can, directly or indirectly, control, modify, or adjust each of these variables.

[0074] In an aspect, the control system is configured to control the flow of the fluid through the nozzle array ejector using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, the fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a fluid flow into the fluid reservoir from the fluid feed system, or a gap distance from the fluid reservoir to the actuator holder.

[0075] In another aspect, the control system is configured to control the flow of the fluid through the nozzle array ejector using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, the fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, or a fluid flow into the fluid reservoir from the fluid feed system.

[0076] In another aspect, the control system is configured to control the flow of the fluid through the nozzle array ejector using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, or a flow rate of the fluid through the nozzle array ejector.

[0077] In another aspect, the control system is configured to control the flow of the fluid through the nozzle array ejector using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude or a measured driving point electrical impedance phase.

[0078] In an aspect, the control system is configured to adjust (e.g., increase or decrease) the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the gap distance from the fluid reservoir to the actuator holder, the optical image of the fluid volume and fluid through the nozzle array ejector, or the ultrasound transmission through the ejected fluid through the nozzle array ejector. In an aspect, the temperature of the fluid in the fluid reservoir is correlated to the temperature of the actuator holder or the transducer stack. The controller system also can use variables such as fluid level or volume in a larger secondary fluid reservoir, which is in fluidic communication with the fluid reservoir.

[0079] In an aspect, the control system is configured to adjust (e.g., increase or decrease) the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the fluid flow into the fluid reservoir from the fluid feed system, or the gap distance from the fluid reservoir to the actuator holder.

[0080] In an aspect, the control system is configured to adjust (e.g., increase or decrease) the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, or the flow rate of the fluid through the nozzle array ejector.

[0081] In an aspect, the control system is configured to adjust (e.g., increase or decrease) the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, or the fluid flow into the fluid reservoir from the fluid feed system.

[0082] In another aspect, the control system is configured to adjust the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude or the driving point measured electrical impedance phase. As described, above, the transducer stack can operate as an actuator and as a driving point electrical impedance sensor. An actuator driver circuit of the transducer stack can be configured to measure the driving point electrical impedance magnitude, the driving point electrical impedance phase, or both. The control system can use this data to in the feedback operation to adjust the flow of the fluid through the nozzle array ejector based.

[0083] In an aspect, the control system can measure when one or more of the following change: the volume of the fluid, the gap distance from the fluid reservoir to the actuator holder, the temperature of the fluid, the fluid level or volume in a larger secondary fluid reservoir which is in fluidic communication with the fluid reservoir or the pressure within the fluid reservoir. When one or more of these variables change, the driving point electrical impedance phase of the transducer stack changes, the driving point electrical impedance magnitude of the transducer stack changes, or both change. As a result, the rate of flow through the nozzle array ejector can be adjusted, the rate of flow of the fluid into the fluid reservoir is adjusted, or both are adjusted using the control system.

[0084] In an aspect, the control system can control the flow rate of the fluid through the nozzle array ejector by changing one or more of the following input signals to the transducer stack: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency. The values of each of these variables are described herein.

[0085] In an aspect, changes in the driving point electrical impedance phase of the transducer stack, the driving point electrical impedance magnitude of the transducer stack, or both can be used to determine the rate of flow through the nozzle array ejector.

[0086] In an aspect, the control system is configured to adjust a gap distance from the transducer stack and the nozzle ejector array based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the optical image of the fluid volume and fluid through the nozzle array ejector, or the ultrasound transmission through the ejected fluid through the nozzle array ejector. Upon adjusting the gap distance, the fluid flow through the nozzle array ejector can be controlled.

[0087] In an aspect, the control system is configured to adjust a gap distance from the transducer stack and the nozzle ejector array based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, or the fluid flow into the fluid reservoir from the fluid feed system. In an aspect, the control system is configured to adjust a gap distance from the transducer stack and the nozzle ejector array based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, or the flow rate of the fluid through the nozzle array ejector.

[0088] In an aspect, the control system is configured to adjust a gap distance from the transducer stack and the nozzle ejector array based on one or more of the following variables: the measured driving point electrical impedance magnitude or the measured driving point electrical impedance phase.

[0089] In an aspect, the device or system can also include one or more of the following additional systems. For example, the device or system can include a pump system used in conjunction with the fluid feeding system, where the pump system can include one or more pumps (e.g., mechanical pump, syringe, or the like) to flow fluid into the fluid reservoir. The device or system can include a larger secondary fluid reservoir which is in fluidic communication with the fluid reservoir to feed fluid to the fluid reservoir. The system can be self-pumping from the secondary reservoir where the flow rate is determined by the fluid flow through the nozzle array ejector. The device or system can include a pressure control system configured to control the pressure in the fluid reservoir. The pressure control system can include one or more sensor to measure the pressure. In an aspect, the pressure control system can use gas flow to increase the pressure or a vacuum to reduce the pressure. The device of system can include a temperature control system configured to control the temperature of the fluid. The temperature control system can include one or more sensors in the fluid reservoir, the actuator holder, and / or the exit of the nozzle array ejector.

[0090] The present disclosure provides for a method of controlling the flow of a fluid. The method includes filling (e.g., using the fluid feeding system) a fluid reservoir with a fluid, where the fluid reservoir is described herein. Then the method includes driving a transducer stack (e.g., as described in reference to the actuator holder), where the transducer stack produces an acoustic wave, a mechanical wave, or both. In response to driving the transducer stack, the method includes flowing the fluid through a nozzle array ejector a flow rate. The step of flowing the fluid through the nozzle array ejector is controlled using a feedback system (e.g., using the control system as described herein) of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a temperature of the fluid, a fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a pressure within the fluid reservoir, a fluid flow into the fluid reservoir from the fluid feed system, a gap distance from the nozzle array ejector to the actuator holder, an optical image of the fluid volume and fluid through the nozzle array ejector, or an ultrasound transmission through the flowed fluid through the nozzle array ejector. These variables are described herein. The method includes when one or more of the variable changes, then the flow rate of the fluid through the nozzle array ejector is adjusted, the fluid flow into the fluid reservoir is adjusted, or both are adjusted.

[0091] In an aspect, the step of flowing the fluid through the nozzle array ejector is controlled using a feedback system (e.g., using the control system as described herein) of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a fluid flow into the fluid reservoir from the fluid feed system, or a gap distance from the nozzle array ejector to the actuator holder.

[0092] In an aspect, the step of flowing the fluid through the nozzle array ejector is controlled using a feedback system (e.g., using the control system as described herein) of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, or a fluid flow into the fluid reservoir from the fluid feed system.

[0093] In an aspect, the step of flowing the fluid through the nozzle array ejector is controlled using a feedback system (e.g., using the control system as described herein) of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, or a flow rate of the fluid through the nozzle array ejector.

[0094] In an aspect, the method includes flowing of the fluid through the nozzle array ejector is adjusted based on one or more of the following variables: the measured driving point electrical impedance magnitude or the driving point measured electrical impedance phase. The method includes when one or more of the variable changes, then the flow rate of the fluid through the nozzle array ejector is adjusted, the fluid flow into the fluid reservoir is adjusted, or both are adjusted.

[0095] In an aspect, the rate of flow through the nozzle array ejector is controlled by changing one or more of the following input signals to the transducer stack: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency. Changes in the driving point electrical impedance phase of the transducer stack, the driving point electrical impedance magnitude of the transducer stack, or both is used to determine the flow rate through the nozzle array ejector. In an aspect, flowing the fluid through the nozzle array ejector is realized when the transducer stack operates in a thickness expansion mode, wherein the transducer stack exhibits substantially (e.g., about 90% or more, about 95% or more) thickness expansion motion.

[0096] In an aspect, flowing the fluid through the nozzle array ejector is realized when the transducer stack operates in a bending vibration mode, wherein when the transducer stack operates substantially in an out of plane bending mode.

[0097] In an aspect, the transducer stack operates as an actuator and as a driving point electrical impedance sensor, where an actuator driver circuit in electrical communication with the transducer stack is configured to measure the driving point electrical impedance magnitude, the driving point electrical impedance phase, or both.

[0098] In an aspect, driving a transducer stack includes using a waveform generator that is in electrical communication with the transducer stack. The waveform generator generates a signal at one or more of the following: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency. Driving the transducer includes operating the transducer stack at: an electrical drive voltage amplitude of about 1 V to 1000 V, an electrical drive current amplitude of about 0.01 A to 5 A, an electrical drive duty cycle for burst operation of about 1% to 99%, an electrical drive signal frequency of about 1 kHz to 10 MHz, or a combination of these.

[0099] In an aspect, the actuator holder includes a mechanical actuator, where the mechanical actuator is capable of changing the gap distance from the transducer stack and the nozzle ejector array.

[0100] In an aspect, the gap distance from the transducer stack and the nozzle ejector array is adjusted based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the optical image of the fluid volume and fluid through the nozzle array ejector, light transmission through the ejected fluid through the nozzle array ejector or the ultrasound transmission through the ejected fluid through the nozzle array ejector.

[0101] Figs. 7 and 8 illustrate two embodiments on implementing continuous operation of the system.

[0102] Now having described various aspects of the present disclosure, the following provide additional description of the present disclosure and various combination of components. Each of the following combination of features (e.g., aspects) are intended to be disclosed by the present disclosure.

[0103] Aspect 1. A system, comprising: a fluid reservoir configured to hold a fluid, wherein the fluid reservoir includes a nozzle array ejector on a first side of the fluid reservoir and the nozzle array ejector is in fluidic communication with the fluid, wherein the fluid reservoir is configured to receive fluid from a fluid feed system; and an actuator holder, wherein the actuator holder includes a transducer stack on a first side of the actuator holder, wherein the actuator holder fits within the fluid reservoir, wherein at least a part of the actuator holder is within the fluid, wherein the first side of the actuator holder is within the fluid and at least one other area of the actuator holder is within the fluid; wherein the fluid is driven from the fluid reservoir through the nozzle array ejector upon actuation of the transducer stack to generate a mechanical wave, an acoustic wave, or both within the fluid reservoir and actuator holder, wherein the acoustic wave, the mechanical wave, or both cause the flow of fluid through the nozzle array ejector, a control system is configured to control the flow of the fluid through the nozzle array ejector using a feedback system of one or more (e.g., two or more, three or more, four or more, five or more, and the like) of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a temperature of the fluid, the fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a pressure within the fluid reservoir, a fluid flow into the fluid reservoir from the fluid feed system, a gap distance from the fluid reservoir to the actuator holder, an optical image of the fluid volume and fluid through the nozzle array ejector, or an ultrasound transmission through the ejected fluid through the nozzle array ejector.

[0104] Aspect 2. The system of aspect 1 and each of the following aspects, wherein the control system is configured to adjust the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the gap distance from the fluid reservoir to the actuator holder, the optical image of the fluid volume and fluid through the nozzle array ejector, or the ultrasound transmission through the ejected fluid through the nozzle array ejector.

[0105] Aspect 3. The system of each of the aspects above and below, wherein the control system is configured to adjust the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude or the driving point measured electrical impedance phase. Aspect 4. The system of each of the aspects above and below, wherein the transducer stack operates as an actuator and as a driving point electrical impedance sensor, wherein an actuator driver circuit of the transducer stack is configured to measure the driving point electrical impedance magnitude, the driving point electrical impedance phase, or both. Aspect 5. The system of each of the aspects above and below, wherein when one or more of the following change: the volume of the fluid, the gap distance from the fluid reservoir to the actuator holder, the temperature of the fluid, or the pressure within the fluid reservoir, then the driving point electrical impedance phase of the transducer stack changes, the driving point electrical impedance magnitude of the transducer stack changes, or both change, then the rate of flow through the nozzle array ejector is adjusted, the rate of flow of the fluid into the fluid reservoir is adjusted, or both are adjusted.

[0106] Aspect 6. The system of each of the aspects above and below, wherein the flow of the fluid is continuous or quasi-continuous.

[0107] Aspect 7. The system of each of the aspects above and below, wherein the flow rate of the fluid through the nozzle array ejector is adjusted by changing one or more of the following input signals to the transducer stack: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency.

[0108] Aspect 8. The system of each of the aspects above and below, wherein changes in the driving point electrical impedance phase of the transducer stack, the driving point electrical impedance magnitude of the transducer stack, or both is used to determine the rate of flow through the nozzle array ejector.

[0109] Aspect 9. The system of each of the aspects above and below, wherein the transducer stack operates in a thickness expansion mode.

[0110] Aspect 10. The system of each of the aspects above and below, wherein the transducer stack exhibits substantially thickness expansion motion.

[0111] Aspect 11. The system of each of the aspects above and below, wherein the transducer stack operates in a bending vibration mode.

[0112] Aspect 12. The system of each of the aspects above and below, wherein the transducer stack operates substantially in an out of plane bending mode.

[0113] Aspect 13. The system of each of the aspects above and below, wherein the actuator holder is a substantially rigid structure at the lateral edges, wherein the transducer stack bends in a vertical direction but expands minimally in the lateral direction which cases the rigid structure to bend during operation of the transducer stack.

[0114] Aspect 14. The system of each of the aspects above and below, wherein the transducer stack includes a transducer and an acoustic coupling structure. Aspect 15. The system of each of the aspects above and below, wherein the transducer includes a piezoelectric transducer or a capacitive transducer.

[0115] Aspect 16. The system of each of the aspects above and below, wherein the fluid reservoir includes a cap structure to limit the total volume of the fluid.

[0116] Aspect 17. The system of each of the aspects above and below, wherein the fluid reservoir includes a droplet accumulation device to limit droplet accumulation on the nozzle array ejector.

[0117] Aspect 18. The system of each of the aspects above and below, wherein the droplet accumulation device has the characteristic of producing a pressure differential across the nozzle array ejector.

[0118] Aspect 19. The system of each of the aspects above and below, further comprising: a waveform generator in electrical communication with the transducer stack, wherein the waveform generator generates a signal at one or more of the following: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency.

[0119] Aspect 20. The system of each of the aspects above and below, wherein the electrical drive voltage amplitude is about 1 V to 1000 V, the electrical drive current amplitude is about 0.01 A to 5 A, the electrical drive duty cycle for burst operation is about 1% to 99%, the electrical drive signal frequency is about 1 kHz to 10 MHz.

[0120] Aspect 21. The system of each of the aspects above and below, wherein the electrical drive signal frequency is at a frequency that is about a frequency of an electromechanical resonance of the system.

[0121] Aspect 22. The system of each of the aspects above and below, further comprising one or more of the following: a pump system including one or more pumps to flow fluid into the fluid reservoir, a pressure control system configured to control the pressure in the fluid reservoir, a temperature control system configured to control the temperature of the fluid. Aspect 23. The system of each of the aspects above and below, wherein the control system is configured to: flow the fluid at a flow rate through the nozzle array ejector based on one or more of the following variables: a measured driving point electrical impedance magnitude, a driving point measured electrical impedance phase, or both.

[0122] Aspect 24. The system of each of the aspects above and below, the actuator holder includes a mechanical actuator, wherein the mechanical actuator is capable of changing the gap distance from the transducer stack and the nozzle ejector array.

[0123] Aspect 25. The system of each of the aspects above and below, wherein the control system is configured to: adjust a gap distance from the transducer stack and the nozzle ejector array based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the optical image of the fluid volume and fluid through the nozzle array ejector, or the ultrasound transmission through the ejected fluid through the nozzle array ejector.

[0124] Aspect 26. The system of each of the aspects above and below, wherein the temperature of the fluid is correlated to the temperature of the actuator holder or the transducer stack.

[0125] Aspect 27. A method of controlling the flow of a fluid, comprising: filling a fluid reservoir with a fluid, wherein the fluid reservoir includes a nozzle array ejector on a first side of the fluid reservoir and the nozzle array ejector is in fluidic communication with the fluid, wherein an actuator holder is within the fluid reservoir, wherein the actuator holder includes a transducer stack on a first side of the actuator holder, wherein the first side of the actuator holder is within the fluid and at least one other area of the actuator holder is within the fluid driving a transducer stack, wherein the transducer stack produces an acoustic wave, a mechanical wave, or both, and flowing the fluid through a nozzle array ejector a flow rate in response to driving the transducer stack, wherein flowing the fluid through the nozzle array ejector is controlled using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a temperature of the fluid, a fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a pressure within the fluid reservoir, a fluid flow into the fluid reservoir from the fluid feed system, a gap distance from the nozzle array ejector to the actuator holder, an optical image of the fluid volume and fluid through the nozzle array ejector, or an ultrasound transmission through the flowed fluid through the nozzle array ejector, wherein when one or more of the variable changes, then the flow rate of the fluid through the nozzle array ejector is adjusted, the fluid flow into the fluid reservoir is adjusted, or both are adjusted.

[0126] Aspect 28. The method of each of the aspects above and below, wherein the flowing of the fluid through the nozzle array ejector is adjusted based on one or more of the following variables: the measured driving point electrical impedance magnitude or the driving point measured electrical impedance phase. Aspect 29. The method of each of the aspects above and below, wherein the flowing of the fluid through the nozzle array ejector is continuous or quasi-continuous.

[0127] Aspect 30. The method of each of the aspects above and below, wherein the rate of flow through the nozzle array ejector is controlled by changing one or more of the following input signals to the transducer stack: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency.

[0128] Aspect 31. The method of each of the aspects above and below, wherein changes in the driving point electrical impedance phase of the transducer stack, the driving point electrical impedance magnitude of the transducer stack, or both is used to determine the flow rate through the nozzle array ejector.

[0129] Aspect 32. The method of each of the aspects above and below, wherein flowing the fluid through the nozzle array ejector is realized when the transducer stack operates in a thickness expansion mode.

[0130] Aspect 33. The method of each of the aspects above and below, wherein flowing the fluid through the nozzle array ejector is realized when the transducer stack exhibits substantially thickness expansion motion.

[0131] Aspect 34. The method of each of the aspects above and below, wherein flowing the fluid through the nozzle array ejector is realized when the transducer stack operates in a bending vibration mode.

[0132] Aspect 35. The method of each of the aspects above and below, wherein flowing the fluid through the nozzle array ejector is realized when the transducer stack operates substantially in an out of plane bending mode.

[0133] Aspect 36. The method of each of the aspects above and below, wherein the transducer stack operates as an actuator and as a driving point electrical impedance sensor, wherein an actuator driver circuit in electrical communication with the transducer stack is configured to measure the driving point electrical impedance magnitude, the driving point electrical impedance phase, or both.

[0134] Aspect 37. The method of claim 27, wherein driving a transducer stack includes using a waveform generator that is in electrical communication with the transducer stack, wherein the waveform generator generates a signal at one or more of the following: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency.

[0135] Aspect 38. The method of each of the aspects above and below, wherein driving the transducer includes operating the transducer stack at: an electrical drive voltage amplitude of about 1 V to 1000 V, an electrical drive current amplitude of about 0.01 A to 5 A, an electrical drive duty cycle for burst operation of about 1% to 99%, an electrical drive signal frequency of about 1 kHz to 10 MHz, or a combination of these.

[0136] Aspect 39. The method of each of the aspects above and below, wherein the actuator holder includes a mechanical actuator, wherein the mechanical actuator is capable of changing the gap distance from the transducer stack and the nozzle ejector array.

[0137] Aspect 40. The method of each of the aspects above and below, wherein the gap distance from the transducer stack and the nozzle ejector array is adjusted based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the optical image of the fluid volume and fluid through the nozzle array ejector, or the ultrasound transmission through the ejected fluid through the nozzle array ejector.

[0138] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a concentration range of “about 0.1% to about 5%” should be interpreted to include not only the explicitly recited concentration of about 0.1 wt% to about 5 wt%, but also include individual concentrations (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within the indicated range. In an embodiment, the term “about” can include traditional rounding according to significant figures of the numerical value. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x’ to about ‘y’”.

[0139] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations, and are merely set forth for a clear understanding of the principles of this disclosure. Many variations and modifications may be made to the above-described embodiment(s) of the disclosure without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

Claims

CLAIMSWe claim:

1. A system, comprising: a fluid reservoir configured to hold a fluid, wherein the fluid reservoir includes a nozzle array ejector on a first side of the fluid reservoir and the nozzle array ejector is in fluidic communication with the fluid, wherein the fluid reservoir is configured to receive fluid from a fluid feed system; and an actuator holder, wherein the actuator holder includes a transducer stack on a first side of the actuator holder, wherein the actuator holder fits within the fluid reservoir, wherein at least a part of the actuator holder is within the fluid, wherein the first side of the actuator holder is within the fluid and at least one other area of the actuator holder is within the fluid; wherein the fluid is driven from the fluid reservoir through the nozzle array ejector upon actuation of the transducer stack to generate a mechanical wave, an acoustic wave, or both within the fluid reservoir and actuator holder, wherein the acoustic wave, the mechanical wave, or both cause the flow of fluid through the nozzle array ejector, a control system is configured to control the flow of the fluid through the nozzle array ejector using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a temperature of the fluid, the fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a pressure within the fluid reservoir, a fluid flow into the fluid reservoir from the fluid feed system, a gap distance from the fluid reservoir to the actuator holder, an optical image of the fluid volume and fluid through the nozzle array ejector, or an ultrasound transmission through the ejected fluid through the nozzle array ejector.

2. The system of claim 1, wherein the control system is configured to adjust the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the gap distance from the fluid reservoir to the actuator holder, the optical image of the fluid volume and fluid through the nozzle array ejector, or the ultrasound transmission through the ejected fluid through the nozzle array ejector.

3. The system of claim 1 , wherein the control system is configured to adjust the flow of the fluid through the nozzle array ejector based on one or more of the following variables: the measured driving point electrical impedance magnitude or the driving point measured electrical impedance phase.

4. The system of claim 1 , wherein the transducer stack operates as an actuator and as a driving point electrical impedance sensor, wherein an actuator driver circuit of the transducer stack is configured to measure the driving point electrical impedance magnitude, the driving point electrical impedance phase, or both.

5. The system of claim 1 , wherein when one or more of the following change: the volume of the fluid, the gap distance from the fluid reservoir to the actuator holder, the temperature of the fluid, or the pressure within the fluid reservoir, then the driving point electrical impedance phase of the transducer stack changes, the driving point electrical impedance magnitude of the transducer stack changes, or both change, then the rate of flow through the nozzle array ejector is adjusted, the rate of flow of the fluid into the fluid reservoir is adjusted, or both are adjusted.

6. The system of claim 1 , wherein the flow of the fluid is continuous or quasi- continuous.

7. The system of claim 6, wherein the flow rate of the fluid through the nozzle array ejector is adjusted by changing one or more of the following input signals to the transducer stack: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency.

8. The system of claim 7, wherein changes in the driving point electrical impedance phase of the transducer stack, the driving point electrical impedance magnitude of the transducer stack, or both is used to determine the rate of flow through the nozzle array ejector.

9. The system of claim 1, wherein the transducer stack operates in a thickness expansion mode.

10. The system of claim 1, wherein the transducer stack exhibits substantially thickness expansion motion.

11. The system of claim 1 , wherein the transducer stack operates in a bending vibration mode.

12. The system of claim 1, wherein the transducer stack operates substantially in an out of plane bending mode.

13. The system of claim 12, wherein the actuator holder is a substantially rigid structure at the lateral edges, wherein the transducer stack bends in a vertical direction but expands minimally in the lateral direction which cases the rigid structure to bend during operation of the transducer stack.

14. The system of claim 1 , wherein the transducer stack includes a transducer and an acoustic coupling structure.

15. The system of claim 14, wherein the transducer includes a piezoelectric transducer or a capacitive transducer.

16. The system of claim 1, wherein the fluid reservoir includes a cap structure to limit the total volume of the fluid.

17. The system of claim 1, wherein the fluid reservoir includes a droplet accumulation device to limit droplet accumulation on the nozzle array ejector.

18. The system of claim 17, wherein the droplet accumulation device has the characteristic of producing a pressure differential across the nozzle array ejector.

19. The system of claim 18, further comprising: a waveform generator in electrical communication with the transducer stack, wherein the waveform generator generates a signal at one or more of the following: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency.

20. The system of claim 19, wherein the electrical drive voltage amplitude is about 1 V to 1000 V, the electrical drive current amplitude is about 0.01 A to 5 A, the electrical drive dutycycle for burst operation is about 1% to 99%, the electrical drive signal frequency is about 1 kHz to 10 MHz.

21. The system of claim 20, wherein the electrical drive signal frequency is at a frequency that is about a frequency of an electromechanical resonance of the system.

22. The system of claim 1 , further comprising one or more of the following: a pump system including one or more pumps to flow fluid into the fluid reservoir, a pressure control system configured to control the pressure in the fluid reservoir, a temperature control system configured to control the temperature of the fluid.

23. The system of claim 1, wherein the control system is configured to: flow the fluid at a flow rate through the nozzle array ejector based on one or more of the following variables: a measured driving point electrical impedance magnitude, a driving point measured electrical impedance phase, or both.

24. The system of claim 1, the actuator holder includes a mechanical actuator, wherein the mechanical actuator is capable of changing the gap distance from the transducer stack and the nozzle ejector array.

25. The system of claim 24, wherein the control system is configured to: adjust a gap distance from the transducer stack and the nozzle ejector array based on one or more of the following variables: the measured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the optical image of the fluid volume and fluid through the nozzle array ejector, or the ultrasound transmission through the ejected fluid through the nozzle array ejector.

26. The system of claim 1 , wherein the temperature of the fluid is correlated to the temperature of the actuator holder or the transducer stack.

27. A method of controlling the flow of a fluid, comprising: filling a fluid reservoir with a fluid, wherein the fluid reservoir includes a nozzle array ejector on a first side of the fluid reservoir and the nozzle array ejector is in fluidic communication with the fluid, wherein an actuator holder is within the fluid reservoir, whereinthe actuator holder includes a transducer stack on a first side of the actuator holder, wherein the first side of the actuator holder is within the fluid and at least one other area of the actuator holder is within the fluid driving a transducer stack, wherein the transducer stack produces an acoustic wave, a mechanical wave, or both, and flowing the fluid through a nozzle array ejector a flow rate in response to driving the transducer stack, wherein flowing the fluid through the nozzle array ejector is controlled using a feedback system of one or more of the following variables: a measured driving point electrical impedance magnitude, a measured driving point electrical impedance phase, a temperature of the fluid, a fluid volume in the fluid reservoir, a flow rate of the fluid through the nozzle array ejector, a pressure within the fluid reservoir, a fluid flow into the fluid reservoir from the fluid feed system, a gap distance from the nozzle array ejector to the actuator holder, an optical image of the fluid volume and fluid through the nozzle array ejector, or an ultrasound transmission through the flowed fluid through the nozzle array ejector, wherein when one or more of the variable changes, then the flow rate of the fluid through the nozzle array ejector is adjusted, the fluid flow into the fluid reservoir is adjusted, or both are adjusted.

28. The method of claim 27, wherein the flowing of the fluid through the nozzle array ejector is adjusted based on one or more of the following variables: the measured driving point electrical impedance magnitude or the driving point measured electrical impedance phase.

29. The method of claim 27, wherein the flowing of the fluid through the nozzle array ejector is continuous or quasi-continuous.

30. The method of claim 29, wherein the rate of flow through the nozzle array ejector is controlled by changing one or more of the following input signals to the transducer stack: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency.

31. The method of claim 30, wherein changes in the driving point electrical impedance phase of the transducer stack, the driving point electrical impedance magnitude of the transducer stack, or both is used to determine the flow rate through the nozzle array ejector.

32. The method of claim 27, wherein flowing the fluid through the nozzle array ejector is realized when the transducer stack operates in a thickness expansion mode.

33. The method of claim 27, wherein flowing the fluid through the nozzle array ejector is realized when the transducer stack exhibits substantially thickness expansion motion.

34. The method of claim 27, wherein flowing the fluid through the nozzle array ejector is realized when the transducer stack operates in a bending vibration mode.

35. The method of claim 27, wherein flowing the fluid through the nozzle array ejector is realized when the transducer stack operates substantially in an out of plane bending mode.

36. The method of claim 27, wherein the transducer stack operates as an actuator and as a driving point electrical impedance sensor, wherein an actuator driver circuit in electrical communication with the transducer stack is configured to measure the driving point electrical impedance magnitude, the driving point electrical impedance phase, or both.

37. The method of claim 27, wherein driving a transducer stack includes using a waveform generator that is in electrical communication with the transducer stack, wherein the waveform generator generates a signal at one or more of the following: an electrical drive voltage amplitude, an electrical drive current amplitude, an electrical drive duty cycle for burst operation, or an electrical drive signal frequency.

38. The method of claim 27, wherein driving the transducer includes operating the transducer stack at: an electrical drive voltage amplitude of about 1 V to 1000 V, an electrical drive current amplitude of about 0.01 A to 5 A, an electrical drive duty cycle for burst operation of about 1% to 99%, an electrical drive signal frequency of about 1 kHz to 10 MHz, or a combination of these.

39. The method of claim 27, wherein the actuator holder includes a mechanical actuator, wherein the mechanical actuator is capable of changing the gap distance from the transducer stack and the nozzle ejector array.

40. The method of claim 39, wherein the gap distance from the transducer stack and the nozzle ejector array is adjusted based on one or more of the following variables: themeasured driving point electrical impedance magnitude, the measured driving point electrical impedance phase, the temperature of the fluid, the fluid volume in the fluid reservoir, the flow rate of the fluid through the nozzle array ejector, the pressure within the fluid reservoir, the fluid flow into the fluid reservoir from the fluid feed system, the optical image of the fluid volume and fluid through the nozzle array ejector, or the ultrasound transmission through the ejected fluid through the nozzle array ejector.

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