Acoustic focusing, transfer and analysis of samples containing particles

Abstract

The systems and methods described herein employ focused acoustic energy applied to a reservoir containing a fluid to eject a fluid sample from the fluid sample reservoir, for example, to an inlet of an analytical device. In many embodiments, the ejected fluid sample traverses an air gap separating the inlet of the analytical device from an upper surface of the fluid in the fluid sample reservoir. In many embodiments, the ejected fluid sample comprises one or more droplets ejected from the fluid sample reservoir, which may contain particles suspended in the fluid sample.

Description

Background Art

[0001] In life science research and clinical diagnosis, analytical detectors are usually used to analyze the size of cells and / or particles configured in fluid samples. In view of the increased demand for analysis of the size of cells and / or particles configured in fluids, high-throughput methods and related systems for analyzing the size of cells and / or particles have attracted attention. Analyzing particles in fluid samples may require that the sample be loaded into a container and diluted to a particle density suitable for analysis, or that bulk fluid properties be compatible with counting and size determination methods. Typically, when particle size determination is performed in a fluid sample, the Coulter principle is applied because it is generally very effective for biological materials (such as cells and viruses) and non-conductive particles. For example, with reference to Coulter counter (U.S. Patent No. 2,656,508), a method for particle counting using the Coulter principle is disclosed to distinguish the presence of non-conductive cells or particles in a conductive fluid.

[0002] Coulter counting uses a conductive solution that forms a conductive path between electrodes, wherein the presence or absence of non-conductive material (e.g., non-conductive cells and / or particles) changes the resistance of the conductive path between the electrodes. If the particle is moving through the electrodes, the change in resistance can be used to determine the particle size. Commercial systems, such as those from Beckman Coulter Inc. (Brea, California), can analyze conductive fluid samples by detecting changes in electrical impedance caused by the presence of particles in the fluid when the particles pass through a measurement area positioned between two electrical terminals.

[0003] However, in the case of Coulter counting, as with other methods of particle counting, sample transfer and sample dilution are potential sources of error or contamination. Therefore, improved methods of sample transfer and dilution of particle-containing samples are desired. Sample transfer methods using acoustic radiation (i.e., acoustic pressure waves) have been described in, for example, U.S. Patent No. 10,156,499. However, reliable transfer of particle-containing fluids for analysis of suspended particles has not been achieved previously. Summary of the invention

[0004] Embodiments disclosed herein include a system having: an acoustic radiation generator; a fluid sample reservoir containing a fluid sample; and an analytical instrument having an inlet that can receive a fluid droplet. The fluid sample reservoir can be acoustically coupled to the acoustic radiation generator through an acoustic coupling medium so that the applied acoustic energy generated by the acoustic radiation generator can be transmitted through the fluid sample reservoir to interact with the fluid sample. The disclosed system and method use the acoustic generator to apply a first burst of focused acoustic radiation to the fluid sample in the fluid sample reservoir to concentrate cells or particles in the fluid sample, and then apply a second burst of focused acoustic radiation by the acoustic radiation generator to the position of the fluid sample corresponding to the concentrated cells or particles, so as to eject a droplet containing at least one cell or particle from the reservoir. The droplet can be ejected to the inlet of an analytical instrument (such as, for example, a cell or particle counter or any other suitable instrument), or the droplet can be transferred for any other suitable purpose, such as, for example, culture splitting, slide loading for microscopy, dilution, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Figure 1A is a simplified schematic diagram of a fluid analysis system according to various embodiments of the present disclosure.

[0006] Figure 1B yes Figure 1A A simplified schematic diagram of a fluid sample analysis system showing a droplet of a fluid sample being ejected from a fluid sample reservoir to an inlet of an analysis device via application of focused acoustic radiation.

[0007] Figure 1C After the fluid sample is ejected from the fluid sample reservoir to the analysis device Figure 1A Simplified schematic diagram of the fluid sample assembly.

[0008] Figure 2 Concentrating cells and / or particles at an upper fluid surface of a fluid sample reservoir via application of focused acoustic radiation prior to ejecting a fluid sample having an increased concentration of cells and / or particles from the fluid sample reservoir is shown.

[0009] Figure 3A , Figure 3B and Figure 3C is a simplified schematic diagram showing an embodiment of a focused acoustic radiation generator coupled to a corresponding fluid sample reservoir, according to an embodiment.

[0010] Figure 4is a simplified schematic diagram of an embodiment of a focused acoustic radiation generator assembly, which includes an annular focused acoustic radiation generating element for applying focused acoustic radiation to concentrate cells and / or particles near the upper surface of the fluid in the fluid sample reservoir and a disk-shaped focused acoustic radiation generating element for applying focused acoustic radiation to eject the fluid sample from the fluid sample reservoir. DETAILED DESCRIPTION

[0011] Various embodiments of the present disclosure include acoustic systems and methods for transferring a fluid containing particles from a sample reservoir to a target location, such as, but not limited to, a sample container, a fluid orifice plate, a sample medium, or an analytical device inlet. For example, the transfer of a fluid sample from a sample reservoir to an analytical detector can be achieved by applying focused acoustic radiation to the fluid in the sample reservoir. The sample reservoir can be positioned to align the fluid surface of the fluid with the inlet of the analytical device and to separate the inlet by a suitable gap.

[0012] Then, focused acoustic radiation emitted in a pattern referred to herein as a burst can be applied to the fluid in the sample reservoir to eject the fluid sample from the sample reservoir so that the ejected fluid sample traverses the gap and enters the inlet of the analytical detector. Many fluid samples are suitable for acoustic transfer, including but not limited to most aqueous solutions. For example, the fluid sample may include a volume of electrolyte in which one or more cells and / or particles are suspended.

[0013] In some embodiments, cells and / or particles suspended within the fluid sample are concentrated near the upper fluid surface via application of focused acoustic radiation to the fluid in the sample reservoir prior to ejecting the fluid sample. By first concentrating the particles and / or cells near the upper fluid surface, the concentration of particles and / or cells within the ejected fluid sample can be increased relative to the average concentration of particles and / or cells within the sample reservoir. The acoustic method is contrasted with the following prior art methods of sample handling for loading a sample for analysis by an analytical device, wherein a typical sample reservoir is placed in fluid communication with an inlet of the analytical device to provide a fluid communication path through which the fluid sample is transferred from the sample reservoir to the analytical device.

[0014] The sample reservoir can be positioned relative to the inlet of the analytical device without direct contact with the inlet of the analytical device, thereby enabling continuous and rapid transfer of fluid samples from multiple reservoirs to the same analytical device, thereby increasing throughput and efficiency, reducing or preventing cross-contamination, and improving sample consistency. In addition, the ability to concentrate cells and / or particles in an ejected fluid sample enables the use of the systems and methods described herein in the purification of fluids.

[0015] In many embodiments, the devices and methods described herein employ focused acoustic energy applied to a reservoir containing a fluid to eject a fluid sample from the fluid sample reservoir to an inlet of an analytical device. In many embodiments, the ejected fluid sample traverses an air gap separating an inlet of the analytical device from an upper surface of the fluid in the fluid sample reservoir. In many embodiments, the ejected fluid sample comprises one or more droplets ejected from the fluid sample reservoir.

[0016] Any suitable analytical device may be used. For example, in some embodiments, the analytical device is adapted to measure the number and size of particles contained within the transferred fluid sample. For example, the detector may use an electrical impedance meter as in a Coulter counter (U.S. Patent 2,656,508) to distinguish the presence of non-conductive cells or particles in a conductive fluid. As an additional example, the detector may be optical and may measure scattered light as in a blood analyzer.

[0017] The devices and methods described herein can be used to provide high-throughput analysis of fluid samples from multiple fluid sample reservoirs by a single analytical detector. For example, the devices and methods described herein can be used to transfer a first fluid sample (e.g., a conductive fluid containing at least one non-conductive particle) from a first reservoir to an inlet aperture of a detector to analyze the first fluid sample (e.g., measure the number and size of particles within the first fluid sample), and then quickly switch to applying focused acoustic energy to a second reservoir to transfer the second fluid sample to the inlet aperture of the detector.

[0018] The devices and methods described herein can be used to increase the concentration of cells and / or particles within an ejected fluid sample. For example, in some embodiments, focused acoustic radiation is applied to a fluid sample reservoir prior to ejecting the fluid sample to concentrate cells and / or particles near the upper surface of the fluid within the fluid sample reservoir. This pre-ejection concentration can be used for any suitable purpose. For example, in order to reduce the total volume of fluid transferred from the sample reservoir to the inlet of the analytical device by the focused acoustic energy, focused acoustic energy can be applied to concentrate particles in a nodal focus region formed near the upper surface of the fluid, and then a pulse of acoustic energy can be applied to the fluid in the sample reservoir to eject the fluid near the nodal focus as droplets, wherein the particle density of the droplets exceeds the average particle density outside the nodal focus point within the fluid.

[0019] In contrast, the rapid succession of focused acoustic ejection of droplets from the reservoir to the measurement aperture can provide only fluid coverage of the aperture. This eliminates the need for a larger amount of fluid to contact the aperture to provide immersion. Drawing fluid through the aperture to perform the measurement can also clean the face of the measurement aperture and prepare the measurement system to receive another sample. After the predetermined volume is transferred to the measurement aperture face, or optionally based on an analysis of the detected particles by the measurement system, the first sample measurement can be completed. The analysis can include, but is not limited to, the total number of particles or the number of particles within a given size range.

[0020] Once a completion criterion is met (i.e., number of droplets of sample transferred or some other analytical criterion), the transfer of droplets from the reservoir is terminated. The device can then be configured to transfer from the next reservoir. The next reservoir can be another container capable of supporting focused acoustic emission, including a detachable container such as a microtube or a connected one, such as wells in a multi-well plate (such as a 384-well or 1536-well microplate, other suitable microplate, or other suitable container).

[0021] Prior to acoustically transferring a droplet from the next sample reservoir, the state of the measuring aperture can be determined to see if the previous sample has been drawn into the interior of the measuring device. This can be done in a variety of ways, such as optically by a camera, or preferably by measuring a signal provided by the aperture itself as the atmosphere near the aperture is drawn into the aperture. Since the current is greatly reduced, the presence of non-conductive gas at the aperture will be easily distinguished from the presence of non-conductive particles in the conductive fluid. The Coulter method typically limits the particle size used for measurement to less than 60% of the diameter of the aperture size to maintain the fidelity of the measurement, in contrast to the gas drawn into the aperture which will span the entire aperture.

[0022] In some embodiments of the invention, this decrease in conductivity due to the absorption of air into the measurement aperture can be coupled with control of the flow rate of the pumping system that draws fluid from the interior region (behind the measurement aperture). For example, when the current flow at the aperture drops below the level generated by the largest particles and consistent with air absorption across the entire aperture, the pump can be turned off when all samples containing fluid have passed through the aperture. In addition, an optional ready signal can be sent to the acoustic droplet generator to indicate that the measurement aperture is in a state suitable for receiving a sample from the next reservoir without risk of contamination.

[0023] Because the measurement aperture face will be repeatedly wetted and de-wetted when the fluid sample is transferred from the reservoir and then drawn into the measurement aperture, it will be desirable that the measurement aperture face include or be coated with a chemically inert resistant and / or non-wetting material that will not retain particles or electrolytes. For example, according to some embodiments, the inlet of the analytical instrument may include a hydrophobic coating, or may be formed of a hydrophobic material, which will cause droplets on the inlet of the analytical instrument to remain coherent until they are drawn through the inlet without leaving residue on the surface of the inlet or breaking into multiple droplets.

[0024] "Low throughput" methods for loading particle analysis instruments combine immersion of the measurement well with large sample volume aspiration and often lack automated sample replacement mechanisms. Even with automation, such methods are limited in speed due to the constraints of long movements from one immersion state to another.

[0025] Turning now to the accompanying drawings, Figure 1A is a simplified schematic diagram of a fluid sample analysis assembly including an acoustic ejector assembly 101, a fluid sample reservoir 103, and an analysis device assembly 105. The ejector assembly 101 may include a focused acoustic radiation generator 113 and a focusing element 115, such as, but not limited to, a concave, diffractive, or annular surface coupled to the acoustic radiation generator 113 and shaped to focus acoustic energy from a focusing element surface 117. The ejector assembly 101 may be acoustically coupled to the fluid sample reservoir 103 via an acoustic coupling medium 119, whereby an acoustic pressure pattern generated by the ejector assembly 101 travels through the acoustic coupling medium into the fluid sample reservoir 103.

[0026] The fluid sample reservoir 103 may include a reservoir body 121, such as, but not limited to, an independent fluid well or tube containing a fluid, a well in a well plate, or any other suitable fluid container. The fluid sample reservoir 103 may be at least partially filled with a fluid sample 123, which optionally contains suspended particles 125. The particles 125 may include, for example, nanoparticles or microparticles, cells, macromolecules, or other suitable particles, as well as mixtures including two or more of the aforementioned particle types combined together as individual particles or any of the aforementioned particle types.

[0027] The fluid sample 123 extends to a fluid surface 127 in the fluid sample reservoir 103, which is positioned to be aligned with the analysis device assembly 105 and positioned at an appropriate distance for fluid transfer from the fluid sample 123 to the analysis device assembly. According to an embodiment, the analysis device assembly 105 is positioned to receive the fluid sample emitted from the fluid sample reservoir 103 via focused acoustic radiation applied to the fluid sample by the acoustic radiation generator 113 and focused by the focusing element 115. Figure 1AAn acoustic radiation generator 113 is shown with a focusing element 115 coupled to a fluid sample reservoir 103 having particles 125 suspended therein.

[0028] Under the control of a controller 107, which may include a computer system (including one or more processors 109 and non-transitory memory 111), the acoustic radiation generator 113 may be enabled to generate acoustic radiation in any number of tone bursts at a wide range of frequencies and / or patterns, with tone burst parameters determining the effect of the tone burst on the fluid sample 123. For example, a first tone burst pattern at a first amplitude may be used to effectuate movement of particles 125 within the fluid sample 123 without ejecting droplets, e.g., to concentrate particles at a fluid surface 127 within a cone-shaped acoustic beam 129 characterized as a tone burst. A second tone burst pattern at a second amplitude, different from the first tone burst pattern, may be used to generate droplets that will separate from the fluid sample 123 at the fluid surface 127, carrying the particles 125.

[0029] The analysis device assembly 105 may include a variety of specific analysis devices or detectors, including but not limited to particle counters. Figure 1A As shown in , the analysis device assembly 105 may include an aperture 152 such as a detector 139 of an analysis device having electrodes 141, 143 positioned on either side of the aperture for sensing a voltage across the length of the aperture and detecting a change in conductivity across the same length from a first electrode 141 positioned outside the detector 139 to a second electrode 143 positioned adjacent a collection chamber 145. In operation, the controller 133, which also includes a processor 135 and a memory device 137, may sense a voltage difference across the electrodes 141, 143 and thereby may measure conductivity through the aperture, wherein a change in conductivity indicates the presence or absence of a particle and, in some cases, the size of the particle. The collected fluid 147 within the collection chamber 145 may be removed at a predetermined rate by a pump 151, which may also be controlled by the controller 133. The acoustic emitter assembly 101 and the analysis device assembly 105 may be controlled by the same control system and accompanying controller, or may be controlled by separate controllers.

[0030] In use, the controller 107 can operate the acoustic ejector assembly 101 to eject droplets from the fluid sample reservoir 103 for analysis by the analysis device assembly 105, such as Figure 1B as shown in . Figure 1B yes Figure 1A1 is a simplified schematic diagram of a fluid sample assembly of FIG. 1 , showing a droplet 153 of a fluid sample 123 ejected from a fluid sample reservoir 103 to an inlet of an aperture 152 of an analysis device assembly 105 via application of focused acoustic radiation by a focused acoustic radiation generator 113. When a droplet 153 is ejected from a fluid surface 127 of the fluid sample 123, the droplet may cross an air gap between the fluid sample reservoir 103 and the analysis device assembly 105 before being deposited at the inlet of the aperture 152 on a detector 139. According to various embodiments, a single droplet containing a particle may be sufficient for analysis, or an accumulation 155 of sample fluid from multiple droplets may be collected to obtain a desired volume of fluid sample 123. When one or more droplets 153 have been collected on the outer surface at the entrance of the hole 152 of the detector 139, the pump 151 can be enabled to draw the accumulation 155 of sample fluid through the hole 152 in order to obtain a particle count or the properties of the particles obtained by analysis, for example, by measuring the electrical impedance within the measurement area of ​​the hole 152, since the electrical impedance is changed by the presence of particles.

[0031] Figure 1C After the fluid sample 123 is ejected from the fluid sample reservoir 103 to the analysis device component 105 Figure 1A A simplified schematic diagram of the fluid sample assembly. Figure 1C In the embodiment of the present invention, no droplets are ejected from the fluid sample reservoir 103, and the micropump 151 has carried away the meniscus of the fluid accumulation 155 of the conductive sample fluid from the surface of the outer electrode 141 in the measurement area of ​​the aperture 152, and thus the electrical contact between the inner electrode 143 and the outer electrode 141 is broken, at which point the controller 133 can signal the pump 151 to stop emptying the collection chamber. Conversely, a new accumulation 155 of sample fluid forms on the outer electrode 141 causing electrical contact between the inner electrode 143 and the outer electrode 141. When electrical contact is reestablished, the conductivity can be detected by the controller 133 and a signal can be sent to re-enable the pump 151.

[0032] The above analysis process can be repeated for samples of particle-containing fluids sequentially ejected from the same reservoir or from different reservoirs, which can be moved to an appropriate position and aligned with the acoustic ejector assembly 101 and the analysis device assembly 105 to facilitate droplet ejection and analysis. Typically, aligning a new reservoir involves orienting the reservoir in at least two dimensions so that the ejected droplets traverse the air gap between the fluid surface 127 and the entrance of the hole 152. In some embodiments, the vertical distance of the fluid reservoir assembly 103 can also be adjusted to align the upper fluid surface 127 of the fluid sample 123 with the focus of the acoustic beam generated by the acoustic radiation generator 113 and focused by the focusing element 115. According to some embodiments, multiple and possibly many fluid sample reservoirs 103 can be quickly positioned, sampled, and repositioned to allow rapid analysis of particle-containing fluids from many fluid reservoirs. The multiple fluid reservoirs may be separate containers that can be individually positioned on a movable stage or other actuator; or may be wells on a multi-well plate or microplate.

[0033] Figure 2 A sample reservoir assembly 200 is shown, showing cells 225 and / or particles concentrated at an upper fluid surface 227 of a fluid sample reservoir via application of focused acoustic radiation, and then ejecting a fluid sample having an increased concentration of cells and / or particles from the fluid sample reservoir. The sample reservoir assembly 200 includes a fluid sample reservoir 103 ( Figures 1A to 1C ) and at least one fluid sample reservoir 203 similar thereto, which may be positioned on or connected to a stage 257 along with one or more other sample reservoirs,

[0034] The acoustic emitter assembly 101 including the acoustic radiation generator 113 coupled to the focusing element 115 can be acoustically coupled to the fluid sample reservoir 203 through the acoustic coupling medium 219. In use, the acoustic emitter assembly 101 can generate a focused acoustic beam 229 to create a nodal concentration 255 of particles or cells 225 near the upper fluid surface 227 of the fluid sample 223. When the particles are focused under the action of the acoustics, the acoustically generated droplets generated from the fluid sample reservoir 203 will have a higher particle concentration than the bulk fluid and reflect the particle density in the focused area near the surface. Methods for how to adjust the frequency of the acoustic radiation within the sample fluid and thus change the wavelength are known to those skilled in the art. The number of nodal and anti-nodal planes selected for efficient particle capture will depend on many factors, including density, particle size, particle stiffness, etc. Dynamic measurement of the fluid thickness by sonar-type methods may be required to maintain the nodal state, and it may also be necessary to change the number of nodal planes as the reservoir fluid depth changes. Such methods for measurement are known to those skilled in the art. Sensing of the resonant state may also be detected according to the method described in, for example, Hueter, Theodor F. and Richard H. Bolt. Sonics: techniques for the use of sound and ultrasound in engineering and science. New York: Wiley, 1955.

[0035] FIG. 3A to FIG. 3C is a simplified cross-sectional schematic diagram showing an embodiment of a focused acoustic radiation generator coupled to a corresponding fluid sample reservoir according to an embodiment. These configurations of the acoustic radiation generator are configured to generate an acoustic radiation pattern suitable for directing suspended particles toward a target volume so as to concentrate the particles near the upper surface of the fluid sample reservoir so as to facilitate the ejection of droplets containing the particles. It should be noted that FIG. 3A to FIG. 3CAt least one of the acoustic generators and focusing elements (or lenses) in each of the embodiments is annular. These acoustic generators and / or focusing elements may include concave focusing piezoelectric elements, reflective or refractive lens elements, or phased array configurations (not shown) or other suitable acoustic wave focusing elements. In these configurations, the shape of the focused beam is primarily controlled by the shape of the lens element, or in the case of a phased array transducer, based on the amplitude and phase of the drive signal provided to the acoustic radiation generator. It should be noted that the shape of the focused beam is optimized to achieve maximum efficiency in guiding particles to the target area. These beam shapes include spherical converging beams, Gaussian beams, and Bessel beams, as well as other suitable beam shapes, for example, as described in Fan, Xudong and Zhang, Likun, Simultaneous trapping and pulling by acoustical Bessel beams as stable tractor beams, The Journal of the Acoustical Society of America 145, 1817 (2019).

[0036] FIG. 3A to FIG. 3C Each of the fluid sample reservoirs 303 containing a fluid sample 323 having suspended particles 324 is shown. The reservoir body 321 of the fluid sample reservoir may extend away from a stage or plate 357 on which the fluid sample reservoir 303 rests, or to which the fluid sample reservoir may be attached. Alternatively, the fluid sample reservoir 303 may be positioned without a sample stage or plate. The fluid sample reservoir 303 may be acoustically coupled to the acoustic emitter 301 via an acoustic coupling medium 319. Preferably, the medium is included to allow free movement of the fluid sample reservoir 303 relative to the acoustic emitter 301.

[0037] exist Figure 3A In the first example arrangement 300a, a ring-shaped acoustic emitter 301a is formed by a combined acoustic radiation generator 313a and a focusing element 315a, whereby the acoustic radiation generator is shaped to have a concave working surface 317a that directs acoustic waves 361 into a coupling medium 319 in a conical shape, so that when the acoustic waves 361 interact with particles 325 in a fluid sample 323, the acoustic waves tend to concentrate the particles at a focal region or node. The fluid sample reservoir 303 can be positioned relative to the acoustic emitter 301a so that the focusing region is located at any suitable location in the fluid sample reservoir 303, typically near the upper surface.

[0038] exist Figure 3BIn the second example arrangement 300b, an annular acoustic emitter 301b is formed by a planar and annular acoustic radiation generator 313b, which is coupled to an annular and curved focusing element 315b, whereby the focusing element has a concave working surface 317b, which directs the acoustic waves 361 into the coupling medium 319 according to a conical pattern similar to the waves generated according to the arrangement 300a.

[0039] Figure 3C A third example arrangement 300c is shown, wherein an annular acoustic emitter 301c formed by an annular acoustic radiation generator 313c transmits acoustic waves into a coupling medium 319, wherein a curved focusing element 317c redirects the acoustic waves to achieve a conical pattern similar to the waves generated according to arrangements 300a or 300b.

[0040] The transducer of FIG. 3 is designed to operate at frequencies at which the acoustic waves generated will guide particles within the relevant size limits toward the target focal area with high efficiency. The drive signal is also optimized to produce a high level of efficacy. The waveform will include a continuous waveform (CW) or long burst tone at the desired frequency to produce an acoustic standing wave pattern to trap particles in a resonant or anti-resonant node of the acoustic field. If necessary, the drive frequency can be slowly swept to provide a means to move it toward the target area. Acoustic waveforms can also be used, which will create an acoustic streaming effect to stir, mix and help guide particles toward the target area. It should also be understood that the above drive mechanisms (particle capture and streaming) used to produce the desired effect can be combined to produce the ultimate efficiency of guiding particles.

[0041] Figure 4is a simplified schematic diagram of an assembly 400 in which a fluid sample reservoir 403 contains a fluid sample 423 having suspended particles 424. A reservoir body 421 of the fluid sample reservoir may extend away from a stage or plate 457 on which the fluid sample reservoir 403 rests or to which the fluid sample reservoir may be attached. Alternatively, the fluid sample reservoir 403 may be positioned without a sample stage or plate. The fluid sample reservoir 403 may be acoustically coupled to the acoustic ejector assemblies 401a and 401b via an acoustic coupling medium 419. The outer annular focused acoustic ejector assembly 401b includes an annular acoustic radiation generator 413b coupled to an annular and concave focusing element 415b having a curved surface 417b to apply focused acoustic radiation to focus cells and / or particles 425 within the fluid sample reservoir 403. Preferably, the suspended particles 425 may be concentrated near the upper surface of the fluid sample 423 within the fluid sample reservoir 403. The inner disk-shaped ejector assembly 401a includes a disk-shaped focused acoustic radiation generator 413a coupled to a focusing element 415a, which may have a concave focusing surface 417 for applying focused radiation to eject the fluid sample from the fluid sample reservoir. In use, the outer ring-shaped focused acoustic ejector assembly 401b may generate a first tone burst of acoustic energy in the form of a first pattern of focused acoustic waves 461b at a pattern, frequency, and amplitude optimized to concentrate the suspended particles 425 in the fluid sample 423 without ejecting droplets. Subsequently, the inner acoustic ejector assembly 401a may generate a second tone burst of focused acoustic energy in the form of a second pattern of focused acoustic waves 461a, typically at a higher amplitude optimized to eject droplets from the surface of the fluid sample 423 and from the same location where the particles 425 are concentrated. Thus, the second tone burst may elevate the fluid sample 423 and separate the particle-containing droplet 453 from the fluid sample 423 .

[0042] Figure 4 The configuration of an acoustic drive mechanism is shown, which combines an acoustic generating device for particle guidance (a transducer with a ring shape) and an acoustic generating device for droplet ejection (a transducer element in the center). It should be noted that for the purpose of optimizing instrument efficiency, it may be necessary for the design and operating frequencies of the guiding transducer and the droplet generating transducer to be different. The geometry in the figure provides the flexibility to optimize the center frequencies of the two generators to be different. It also enables independent beam shape designs for the two generators. In many embodiments, the annular ring focused acoustic radiation generating element and the disk-shaped focused acoustic radiation generating element have different thicknesses, which indicate the different frequencies of the sounds they generate, where the inner disk is thinner for droplets and the outer ring is thicker for creating desired particle motions such as mixing, deagglomeration, capture or concentration through node concentration fields.

[0043] Although it should be understood that Figure 4The geometry allows for greater flexibility in the independent design of the particle guidance transducer and the droplet ejection transducer, but it is also possible to combine them in a single transducer, providing acoustic drive for both functionalities.

[0044] Sample Application

[0045] Example 1: The device shown in Figure 1 can be implemented with a control device (not shown) to achieve rapid cleaning and / or quality control of containers that may contain particles. The signal generated by the electrodes across the measurement area and transmitted to the analyzer via the conductor can serve as an input to the decision device, which can control the micropump, the acoustic radiation generator and the positioning device for all related parts of the system, including but not limited to aligning or exchanging the sample fluid container / reservoir, exchanging or aligning (i.e., focusing it at the fluid surface) the acoustic radiation generator, or even changing the aperture assembly so that the diameter of the measurement area is appropriate for the expected particle size in the fluid in the sample container.

[0046] The control device in this embodiment will prepare the fluid sample by mixing or concentrating particles in the focal area so that droplets are transferred. Then, the control device will command the micro pump to start moving the fluid present at the external electrode through the measurement area. The generated signal is sent to the analyzer, and then processed by the control device to determine how to change both the droplet generation rate and the micro pump flow rate to achieve a predetermined goal. For example, the process can continue until a predetermined number of droplets or total fluid volume has been transferred and the particle data has been recorded as a part of the quality control program. Similarly, the control device can process the particle data and determine whether to stop the transfer or continue based on many standards (such as the number of particles detected per unit time or volume, the number of particles detected per unit time or volume within a given size range, etc.). This system configuration, when coupled with the ability to concentrate particles near the focus, will enable the present invention to operate to efficiently extract particles from the container, and stop the transfer process when the data provided to the control device from the analyzer meets the desired standard.

[0047] As used in this specification and the appended claims, indefinite and definite articles in the singular include plural referents as well, unless the context clearly dictates otherwise. Thus, for example, reference to "a reservoir" includes a single reservoir as well as a plurality of reservoirs, reference to "a fluid" includes a single fluid as well as a plurality of fluids, reference to "a frequency range" includes a single frequency range as well as a plurality of ranges, and reference to "an ejector" includes a single ejector as well as a plurality of ejectors, etc.

[0048] It should be understood that the present invention is not limited to specific fluids, frequency ranges or device structures, and therefore may vary. It should be understood that although the present invention has been described in conjunction with a plurality of specific embodiments, the foregoing description is intended to illustrate rather than limit the scope of the present invention. Other aspects, advantages and modifications will be apparent to those skilled in the art. All patents, patent applications, journal articles and other references cited herein are incorporated by reference in their entirety.

[0049] In the following, more examples are described to facilitate understanding of the present invention:

[0050] Example A: A system for acoustically ejecting droplets containing particles, the system comprising:

[0051] Acoustic radiation generator;

[0052] a fluid sample reservoir, the fluid sample reservoir containing a fluid sample, the fluid sample reservoir being acoustically coupled to the acoustic radiation generator via an acoustic coupling medium; and

[0053] A controller comprising one or more processors and a memory device containing executable instructions that, when executed by the one or more processors, configure the controller to:

[0054] applying a first burst of focused acoustic radiation from the acoustic radiation generator to the fluid sample in the fluid sample reservoir to focus cells or particles in the fluid sample; and

[0055] A second burst of focused acoustic radiation is applied by the acoustic radiation generator to a target location of the fluid sample corresponding to the concentrated cells or particles to eject a droplet containing at least one cell or particle from the reservoir.

[0056] Example B: A system as described in any of the preceding examples, the system also includes an analysis device having an inlet positioned to be aligned with the acoustic radiation generator so that when the droplet is ejected from the reservoir, the droplet contacts the inlet.

[0057] Example C: A system as described in Example B, wherein the analysis device includes an electrolytic particle counter configured to count or measure suspended particles by measuring the electrical impedance of a fluid containing particles across a hole.

[0058] Example D: The system of Example B, wherein the analysis device includes a visual particle counter configured to count or measure the suspended particles by optically identifying the suspended particles.

[0059] Example E: The system of any of the preceding examples, further comprising: a second fluid sample reservoir containing a second fluid sample; and an actuator configured to move the second fluid sample reservoir relative to the acoustic radiation generator, wherein the executable instructions, when executed by the one or more processors, further configure the controller to:

[0060] causing the actuator to position the second fluid sample reservoir into alignment with the acoustic radiation generator after ejecting the droplet from the reservoir;

[0061] applying a third tone burst of focused acoustic radiation from the acoustic radiation generator to the second fluid sample in the second sample reservoir to focus cells or particles in the second fluid sample; and

[0062] A fourth burst of focused acoustic radiation is applied by the acoustic radiation generator to a target position of the second sample fluid in the second sample reservoir corresponding to the concentrated cells or particles to eject a second droplet containing at least one cell or particle from the second sample reservoir.

[0063] Example F: A system as described in any of the preceding examples, wherein the acoustic radiation generator includes: an annular element configured to focus the first sound burst to concentrate the cells or particles; and a disk-shaped element concentric within the annular element, the disk-shaped element configured to focus the second sound burst to eject the droplet, wherein:

[0064] The first tone burst is applied via the annular element; and

[0065] The second tone burst is applied via the disk-shaped element.

[0066] Example G: A method for acoustically transferring a fluid droplet containing particles, the method comprising:

[0067] applying a first tone burst of focused acoustic radiation from an acoustic radiation generator to a fluid sample containing suspended cells or particles in a fluid sample reservoir, such that the first tone burst concentrates the cells or particles at a target location within the fluid sample; and

[0068] A second burst of focused acoustic radiation is applied by the acoustic radiation generator to the target location of the fluid sample corresponding to the concentrated cells or particles to eject a droplet containing at least one cell or particle from the reservoir.

[0069] Example H: A method as described in any of the preceding examples, further comprising:

[0070] Prior to applying the second tone burst, positioning the fluid sample reservoir in alignment with an inlet of an analytical device; and

[0071] The droplet is ejected from the fluid sample reservoir such that the droplet contacts the inlet of the analytical device.

[0072] Example I: The method of Example H, wherein the analysis device comprises a particle counter having a detector configured to count cells or particles, the method further comprising:

[0073] Particle counting is performed on the droplets contacting the inlet of the analytical device.

[0074] Example J: A method as described in any of the preceding examples, wherein the first tone burst and the second tone burst are applied sequentially.

[0075] Example K: A method as described in any of the preceding examples, further comprising:

[0076] The first tone burst is repeatedly applied to maintain an increased concentration of the cells or particles at the target location within the fluid sample.

[0077] Example L: A method as described in any of the preceding examples, wherein the first tone burst comprises one of a continuous waveform or a long tone burst, wherein the continuous waveform or the long tone burst is configured to generate an acoustic standing wave in the fluid sample to trap the cells or the particles in a resonant or anti-resonant node.

[0078] Example M: ​​A method as described in any of the preceding examples, wherein the first tone burst includes a frequency sweep configured to push the cell or particle toward the target location within the fluid sample.

[0079] Example N: The method as described in any of the above examples, further comprising:

[0080] positioning a second fluid sample reservoir containing a second fluid sample in alignment with the acoustic radiation generator after ejecting the droplet from the reservoir;

[0081] applying a third tone burst of focused acoustic radiation from the acoustic radiation generator to the second fluid sample to focus cells or particles within the second fluid sample; and

[0082] A fourth burst of focused acoustic radiation is applied by the acoustic radiation generator to a second target position of the second sample fluid in the second sample reservoir corresponding to the concentrated cells or particles, so as to eject a second droplet containing at least one cell or particle from the second sample reservoir.

[0083] Example O: A method as described in any of the preceding examples, wherein:

[0084] The sound radiation generator includes a first annular sound radiation generator and a second disk-shaped sound radiation generator positioned concentrically with the first sound radiation generator;

[0085] The first tone burst is generated by the first acoustic radiation generator; and

[0086] The second tone burst is generated by the second acoustic radiation generator.

[0087] Example P: A method as described in any of the preceding examples, further comprising:

[0088] The vertical position of the fluid sample reservoir is adjusted to align a focal area of ​​the first tone burst or the second tone burst with an upper surface of the fluid sample.

[0089] Example Q: A system comprising:

[0090] Acoustic radiation generator;

[0091] a fluid sample reservoir, the fluid sample reservoir containing a fluid sample, the fluid sample reservoir being acoustically coupled to the acoustic radiation generator via an acoustic coupling medium;

[0092] an analytical instrument comprising an inlet configured to receive a fluid droplet; and

[0093] A controller comprising one or more processors and a memory device containing executable instructions that, when executed by the one or more processors, configure the controller to:

[0094] applying a first burst of focused acoustic radiation from the acoustic radiation generator to the fluid sample in the fluid sample reservoir to focus cells or particles in the fluid sample; and

[0095] A second tone burst of focused acoustic radiation is applied by the acoustic radiation generator to a target location of the fluid sample corresponding to the concentrated cells or particles to eject a droplet containing at least one cell or particle from the reservoir to the inlet of the analytical instrument.

[0096] Example R: A system as in any of the preceding examples, wherein:

[0097] The analytical instrument includes a particle counter having a detector configured to count cells or particles; and

[0098] The executable instructions, when executed by the one or more processors, further configure the controller to:

[0099] After ejecting the droplet from the fluid sample reservoir to the inlet, the analytical instrument is caused to perform a particle count on the transferred fluid sample including the ejected droplet.

[0100] Example S: A system as in any of the preceding examples, wherein:

[0101] The analytical instrument comprises a pump fluidly connected to the inlet of the analytical device; and

[0102] The executable instructions, when executed by the one or more processors, further configure the controller to:

[0103] detecting, via the detector, the presence of an ejected droplet at the inlet; and

[0104] in response to detecting the ejected droplet, causing the pump to draw fluid through the inlet;

[0105] Example T: The system of any of the preceding examples, wherein the inlet of the analytical instrument comprises a non-wetting material that prevents residue from being retained at the inlet.

[0106] Example U: A method for acoustically transferring a fluid droplet containing particles, the method comprising:

[0107] positioning a fluid sample reservoir containing a fluid sample having suspended cells or particles in alignment with an inlet of an analytical device configured for counting cells or particles, the fluid sample reservoir being acoustically coupled to an acoustic radiation generator; and

[0108] The acoustic radiation generator applies an ejection burst of focused acoustic radiation to the fluid sample in the fluid sample reservoir to eject a droplet from the fluid sample reservoir so that the droplet contacts the inlet of the analysis device, wherein the droplet contains at least one cell or particle.

[0109] Example V: The method as described in Example U, further comprising:

[0110] Prior to applying the ejection burst tone, the cells or particles are concentrated at a target position within the fluid sample by applying a concentrated burst tone of focused acoustic radiation to the fluid sample by the acoustic radiation generator, wherein the concentrated burst tone is configured to move the cells or particles toward the target position within the fluid sample without causing droplet ejection.

[0111] Example W. A method as described in any of the preceding examples, wherein the concentrated tone burst and the ejected tone burst are applied sequentially.

[0112] Example X. The method of any of the preceding examples, further comprising:

[0113] The focused tone burst is repeatedly applied to maintain an increased concentration of the cells or particles at the target location within the fluid sample.

[0114] Example Y. A method as described in any of the preceding examples, wherein the concentrated tone burst comprises one of a continuous waveform or a long tone burst, wherein the continuous waveform or the long tone burst is configured to generate an acoustic standing wave in the fluid sample to trap the cells or the particles in a resonant or anti-resonant node.

[0115] Example Z. A method as described in any of the preceding examples, wherein the focused tone burst includes a frequency sweep configured to push the cells or particles toward the target location within the fluid sample.

[0116] Example AA. A method as described in any of the preceding examples, wherein:

[0117] The sound radiation generator includes a first annular sound radiation generator and a disk-shaped second sound radiation generator positioned concentrically with the first sound radiation generator;

[0118] The concentrated burst sound is generated by the first acoustic radiation generator; and

[0119] The ejection burst sound is generated by the second acoustic radiation generator.

[0120] Example AB. The method of any of the preceding examples, further comprising:

[0121] After ejecting the droplet from the fluid sample reservoir, positioning a second fluid sample reservoir containing a second fluid sample in alignment with the acoustic radiation generator;

[0122] applying a second concentrated burst of focused acoustic radiation to the second fluid sample by the acoustic radiation generator to concentrate cells or particles in the second fluid sample; and

[0123] A second ejection burst of focused acoustic radiation is applied by the acoustic radiation generator to a second target position of the second sample fluid in the second fluid sample reservoir corresponding to the concentrated cells or particles, so as to eject a second droplet containing at least one cell or particle from the second fluid sample reservoir.

[0124] Example AC. The method of any of the preceding examples, further comprising:

[0125] The vertical position of the fluid sample reservoir is adjusted to align a focal region of the emission tone burst with an upper surface of the fluid sample.

[0126] Example AD. A method as described in any of the preceding examples, further comprising:

[0127] Particle counting is performed by the analyzing device on the droplets contacting the inlet of the analyzing device.

[0128] Example AE. The method of Example AD, wherein:

[0129] The analytical device comprises an electrolytic particle counter configured to count or measure suspended particles by measuring electrical impedance of a fluid containing cells or particles across a well of the analytical device fluidically coupled to the inlet; and

[0130] Performing the particle count includes electrically sensing the passage of the cell or particle through the aperture from the droplet contacting the inlet.

[0131] Example AF. The method of example AE, further comprising:

[0132] ejecting additional subsequent droplets from the fluid sample contained in the fluid sample reservoir to replenish the droplets contacting the inlet of the analytical device; and

[0133] Ejection of the additional subsequent droplets from the fluid sample is ceased based on a property of the particle count.

[0134] Example AG. A method as described in Example AF, wherein the attribute of the particle count is one of: the number of cells or particles, the size of the cells or particles, the number of cells or particles per unit time, the number of cells or particles within a predetermined size range, or the total volume passing through the analytical device.

[0135] Example AH. A system for acoustically ejecting droplets containing particles, the system comprising:

[0136] Acoustic radiation generator;

[0137] a fluid sample reservoir, the fluid sample reservoir containing a fluid sample, the fluid sample reservoir being acoustically coupled to the acoustic radiation generator via an acoustic coupling medium;

[0138] an analytical device configured for counting cells or particles, the analytical device comprising an inlet positioned in alignment with at least one of the acoustic radiation generator and the fluid sample reservoir; and

[0139] A controller comprising one or more processors and a memory device containing executable instructions that, when executed by the one or more processors, configure the controller to:

[0140] An ejection burst of focused acoustic radiation is applied by the acoustic radiation generator to a target location of the fluid sample to eject a droplet containing at least one cell or particle from the fluid sample reservoir so that the droplet contacts the inlet of the analytical device.

[0141] Example AI. The system of Example AH, wherein the executable instructions, when executed by the one or more processors, further configure the controller to:

[0142] Prior to applying the ejection burst tone, the cells or particles are concentrated at the target location within the fluid sample by applying a concentrated burst tone of focused acoustic radiation by the acoustic radiation generator to the fluid sample in the fluid sample reservoir, so as to concentrate the cells or particles at the target location within the fluid sample without causing droplet ejection.

[0143] Example AJ. A system as described in any of the preceding examples, wherein the acoustic radiation generator includes: an annular element configured to focus the concentrated sound burst to focus the cells or particles; and a disk-shaped element concentric within the annular element, the disk-shaped element configured to focus the ejection sound burst to eject the droplet, wherein:

[0144] The concentrated tone burst is applied via the annular element; and

[0145] The ejection tone burst is applied via the disk-shaped element.

[0146] Example AK. The system of any of the preceding claims, wherein the executable instructions, when executed by the one or more processors, further configure the controller to:

[0147] applying subsequent additional ejection bursts to eject additional subsequent droplets from the fluid sample contained in the fluid sample reservoir to supplement the droplets contacting the inlet of the analytical device;

[0148] causing the analytical device to obtain a particle count of cells or particles contained in the droplet contacting the inlet of the analytical device; and

[0149] The ejection of the additional subsequent droplets is stopped based on the attribute of the particle count.

[0150] Example AL. A system as described in Example AK, wherein the attribute of the particle count is one of: the number of cells or particles, the size of the cells or particles, the number of cells or particles per unit time, the number of cells or particles within a predetermined size range, or the total volume passing through the analytical device.

[0151] Example AM. The system of any of the preceding examples, further comprising: a second fluid sample reservoir containing a second fluid sample; and an actuator configured to move the second fluid sample reservoir relative to the acoustic radiation generator, wherein the executable instructions, when executed by the one or more processors, further configure the controller to:

[0152] After ejecting the droplet from the fluid sample reservoir, causing the actuator to position the second fluid sample reservoir into alignment with the acoustic radiation generator; and

[0153] A second ejection burst of focused acoustic radiation is applied by the acoustic radiation generator to the second sample fluid in the second fluid sample reservoir to eject a second droplet from the second fluid sample reservoir, so that the second droplet contacts the inlet of the analysis device.

[0154] Example AN. A system as described in any of the preceding examples, wherein:

[0155] The second fluid sample includes additional cells or particles; and

[0156] The executable instructions, when executed by the one or more processors, further configure the controller to:

[0157] The additional cells or particles are concentrated by applying a second concentrated burst of focused acoustic radiation by the acoustic radiation generator to the second fluid sample in the second fluid sample reservoir.

[0158] Example AO. A system as described in any of the preceding examples, wherein the analysis device includes one of: an electrolytic particle counter configured to count or measure suspended cells or particles by measuring the electrical impedance of a particle-containing fluid on both sides of a hole fluidically connected to the inlet; or a visual particle counter configured to count or measure suspended cells or particles by optically identifying at least one cell or particle contained in the ejected droplets that contact the inlet.

Claims

1. A method for acoustically transferring a fluid droplet containing particles, the method comprising: positioning a fluid sample reservoir containing a fluid sample having suspended cells or particles in alignment with an inlet of an analytical device configured for counting cells or particles, the fluid sample reservoir being acoustically coupled to an acoustic radiation generator; as well as applying an ejection burst of focused acoustic radiation to the fluid sample in the fluid sample reservoir by the acoustic radiation generator to eject a droplet from the fluid sample reservoir so that the droplet contacts the inlet of the analysis device, wherein the droplet contains at least one cell or particle, The method further includes: before applying the ejection burst tone, concentrating the cells or particles at a target position within the fluid sample by applying a concentrated burst tone of focused acoustic radiation to the fluid sample by the acoustic radiation generator, wherein the concentrated burst tone is configured to move the cells or particles toward the target position within the fluid sample so that the cells or particles have an increased concentration at the target position without causing droplet ejection.

2. The method of claim 1, wherein the concentrated tone burst and the ejected tone burst are applied sequentially.

3. The method of claim 1, further comprising: The focused tone burst is repeatedly applied to maintain the increased concentration of the cells or particles at the target location within the fluid sample.

4. The method of claim 1, wherein the concentrated tone burst comprises one of a continuous waveform or a long tone burst configured to generate an acoustic standing wave in the fluid sample to trap the cells or the particles in a resonant or anti-resonant node.

5. The method of claim 1, wherein the focused tone burst comprises a frequency sweep configured to push the cells or particles toward the target location within the fluid sample.

6. The method of claim 1, wherein: The sound radiation generator includes a first annular sound radiation generator and a disk-shaped second sound radiation generator positioned concentrically with the first sound radiation generator; The concentrated burst sound is generated by the first acoustic radiation generator; and The ejection burst sound is generated by the second acoustic radiation generator.

7. The method of claim 1, further comprising: After ejecting the droplet from the fluid sample reservoir, positioning a second fluid sample reservoir containing a second fluid sample in alignment with the acoustic radiation generator; applying a second concentrated burst of focused acoustic radiation to the second fluid sample by the acoustic radiation generator to concentrate cells or particles in the second fluid sample; as well as A second ejection burst of focused acoustic radiation is applied by the acoustic radiation generator to a second target position of the second fluid sample in the second fluid sample reservoir corresponding to concentrated cells or particles, so as to eject a second droplet containing at least one cell or particle from the second fluid sample reservoir.

8. The method according to any one of claims 1 to 7, further comprising: The vertical position of the fluid sample reservoir is adjusted to align a focal region of the emission tone burst with an upper surface of the fluid sample.

9. The method according to any one of claims 1 to 7, further comprising: Particle counting is performed by the analysis device on droplets contacting the inlet of the analysis device.

10. The method of claim 9, wherein: The analytical device includes an electrolytic particle counter configured to count or measure suspended cells or particles in the droplet contacting the inlet of the analytical device by measuring the electrical impedance of fluid drawn from the droplet across an aperture of the analytical device fluidically coupled to the inlet; and Performing particle counting includes electrically sensing the passage of cells or particles through the aperture from the droplet contacting the inlet.

11. The method of claim 9, further comprising: ejecting additional subsequent droplets from the fluid sample contained in the fluid sample reservoir to replenish the droplet contacting the inlet of the analytical device; as well as Ejection of the additional subsequent droplets from the fluid sample is ceased based on a property of the particle count.

12. The method of claim 11, wherein the attribute of the particle count is one of: the number of cells or particles, the size of cells or particles, the number of cells or particles per unit time, the number of cells or particles within a predetermined size range, or the total volume passing through the analytical device.

13. A system for acoustically ejecting droplets containing particles, the system comprising: Acoustic radiation generator; a fluid sample reservoir, the fluid sample reservoir containing a fluid sample, the fluid sample reservoir being acoustically coupled to the acoustic radiation generator via an acoustic coupling medium; an analytical device configured for counting cells or particles, the analytical device comprising an inlet positioned in alignment with at least one of the acoustic radiation generator and the fluid sample reservoir; as well as A controller comprising one or more processors and a memory device containing executable instructions that, when executed by the one or more processors, configure the controller to: applying an ejection burst of focused acoustic radiation from the acoustic radiation generator to a target position of the fluid sample to eject a droplet containing at least one cell or particle from the fluid sample reservoir so that the droplet contacts the inlet of the analysis device, Wherein, the executable instructions, when executed by the one or more processors, further configure the controller to: Prior to applying the ejection burst tone, the cells or particles are concentrated at the target location in the fluid sample by applying a concentrated burst tone of focused acoustic radiation by the acoustic radiation generator to the fluid sample in the fluid sample reservoir, thereby concentrating the cells or particles in the fluid sample at the target location so that the cells or particles have an increased concentration at the target location without causing droplet ejection.

14. The system of claim 13, wherein the acoustic radiation generator comprises: an annular element configured to focus the concentrated tone burst to focus the cells or particles; and a disk-shaped element, the disk-shaped element being concentric within the annular element, the disk-shaped element being configured to focus the ejection burst to eject the droplet, wherein: The concentrated tone burst is applied via the annular element; and The ejection tone burst is applied via the disk-shaped element.

15. The system of any one of claims 13 to 14, further comprising: a second fluid sample reservoir containing a second fluid sample; and an actuator configured to move the second fluid sample reservoir relative to the acoustic radiation generator, wherein the executable instructions, when executed by the one or more processors, further configure the controller to: causing the actuator to position the second fluid sample reservoir into alignment with the acoustic radiation generator after ejecting the droplet from the fluid sample reservoir; as well as A second ejection burst of focused acoustic radiation is applied by the acoustic radiation generator to the second fluid sample in the second fluid sample reservoir to eject a second droplet from the second fluid sample reservoir, so that the second droplet contacts the inlet of the analysis device.

16. The system of claim 15, wherein: The second fluid sample includes additional cells or particles; and The executable instructions, when executed by the one or more processors, further configure the controller to: The additional cells or particles are concentrated by applying a second concentrated burst of focused acoustic radiation to the second fluid sample in the second fluid sample reservoir by the acoustic radiation generator.

17. The system of any one of claims 13 to 14, wherein the executable instructions, when executed by the one or more processors, further configure the controller to: applying subsequent additional ejection bursts to eject additional subsequent droplets from the fluid sample contained in the fluid sample reservoir to supplement the droplets contacting the inlet of the analytical device; causing the analytical device to obtain a particle count of cells or particles contained in the droplet contacting the inlet of the analytical device; and The ejection of the additional subsequent droplets is stopped based on the attribute of the particle count.

18. The system of claim 17, wherein the attribute of the particle count is one of: the number of cells or particles, the size of cells or particles, the number of cells or particles per unit time, the number of cells or particles within a predetermined size range, or the total volume passing through the analytical device.

19. A system as described in any one of claims 13 to 14, wherein the analytical device comprises one of the following: an electrolytic particle counter, which is configured to count or measure suspended cells or particles by measuring the electrical impedance of a particle-containing fluid on both sides of a hole fluidically connected to the inlet; or a visual particle counter, which is configured to count or measure suspended cells or particles by optically identifying at least one cell or particle contained in the ejected droplet that contacts the inlet.

20. A method for acoustically transferring a fluid droplet containing particles, the method comprising: applying, by an acoustic radiation generator, a first tone burst of focused acoustic radiation to a fluid sample containing suspended cells or particles in a fluid sample reservoir, such that the first tone burst concentrates the cells or particles at a target location within the fluid sample and the cells or particles have an increased concentration at the target location; as well as A second burst of focused acoustic radiation is applied by the acoustic radiation generator to the target location of the fluid sample corresponding to the concentrated cells or particles to eject a droplet containing at least one cell or particle from the fluid sample reservoir.

21. A system for acoustically ejecting droplets containing particles, the system comprising: Acoustic radiation generator; a fluid sample reservoir, the fluid sample reservoir containing a fluid sample, the fluid sample reservoir being acoustically coupled to the acoustic radiation generator via an acoustic coupling medium; as well as A controller comprising one or more processors and a memory device containing executable instructions that, when executed by the one or more processors, configure the controller to: applying a first burst of focused acoustic radiation from the acoustic radiation generator to the fluid sample in the fluid sample reservoir to concentrate cells or particles in the fluid sample so that the cells or particles have an increased concentration at a target location; as well as A second burst of focused acoustic radiation is applied by the acoustic radiation generator to the target location of the fluid sample corresponding to the concentrated cells or particles to eject a droplet containing at least one cell or particle from the fluid sample reservoir.

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