WO2025264457A1 - Mixing using frequency-modulated standing waves - Google Patents

Abstract

Methods and systems are provided to facilitate non-contact mixing of patient samples and reagents via pulsed ultrasound. A liquid mixing system includes cuvettes that hold a fluid to be mixed and at least a first active ultrasound source configured to emit a first ultrasonic transmission through a first face and a second ultrasound source configured to emit an opposing second ultrasonic transmission to create a standing wave within the fluid. A driver circuit is configured to control the operation of the ultrasonic elements and to modulate the standing wave pattern using frequency modulation.

Description

MIXING USING FREQUENCY-MODULATED STANDING WAVES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application Serial No. 63/661,759, filed on June 19, 2024, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[0002] The present disclosure relates generally to methods, systems, and apparatus for mixing fluids and more specifically to using ultrasonic sources to create pressure gradients within a fluid.

BACKGROUND

[0003] Mixing and homogenization of reagents and samples is a common and important task in in vitro diagnostics (IVD) systems. Mixing in a clinical chemistry (CC) reaction ring, for example, is commonly performed using a mechanical mixer comprising an impeller that is introduced into the cuvette and spun at sufficiently high speeds for a sufficient duration. Although effective, this method is plagued by several disadvantages and risk factors that include: (a) additional cycle time required to position and introduce impeller into the cuvette, mix, retract the impeller after the mixing operation, and wash the impeller before reuse; (b) reagent carryover by the probe or impeller due to probe-to-cuvette misalignment; (c) need for washing probes/impellers; (d) critical dependence of mixing performance on mixer-to-cuvette alignment, (e) high total cost of ownership (TCO).

[0004] There has been some work in using non-contact methods of mixing, such as ultrasonic mixing using a transducer outside the cuvette. For example, US Patent 7,955,557 teaches using acoustic radiation pressure from a transducer on the side and bottom of a reaction vessel/cuvette. This surface swells up by the action of the horizontally oriented transducer and the vertical radiation from the bottom transducer (or reflector). The horizontal and vertical waves together create motion in the fluid. The motion helps mix the fluids. EP Patent 1340535 teaches a similar system where a slightly downward-facing reflector opposite the horizontal-facing transducer reflects the horizontal acoustic radiation back into the fluid after the acoustic radiation has crossed the fluid. This reflection is directed at a downw ard angle, aw ay from the free surface of the fluid to help create motion in the fluid. US Patent 10,737.228 teaches phase modulation of the transducer input to induce a time-dependent modulation of a standing-wave pattern generated to induce mixing, but mixing efficiency still leaves room for improvement.

[0005] These prior examples do not mention controlling attributes of the ultrasonic waves based on the resonant properties of the fluid being mixed. Nor do they maximize movement of bulk fluid portions of the fluid to optimize mixing. Accordingly, there remains room for improvement in ultrasonic mixing for IVD tasks.

SUMMARY

[0006] Disclosed mixing methods and systems use ultrasonic energy in anon-contact method that mitigates carryover and contamination risks. Furthermore, this can relax requirements on the mechanical assembly imposed by impeller alignment requirements, can entail lower cost of ownership due to superior reliability’ and reduced service costs, and can afford significant savings in cycle time by eliminating operations in the sequence associated with positioning and introduction of moves in and out of the cuvette of the mixer impeller. Further, ultrasonic mixing can be employed to mix small volumes of reagent and sample whereas the mechanical mixer (impeller) is challenged in this regime.

[0007] In an exemplary embodiment, liquid mixing system includes a cuvette configured to hold a fluid to be mixed and a first ultrasound source situated on one side of the cuvette and configured to emit a first ultrasonic transmission (which can be substantially planar) substantially horizontally through a first face of the cuvette through the fluid at an ultrasonic frequency. A second ultrasound source is situated on an opposite side of the cuvette and configured to emit a second ultrasonic transmission at the ultrasonic frequency such that the first and second ultrasonic transmissions form a standing wave in the fluid. A driver circuit is configured to control the operation of at least the first ultrasound source and to modulate the ultrasonic frequency to create a standing wave pattern of high and low-pressure nodes within the fluid that changes during mixing.

[0008] In some embodiments, the driver circuit modulates the ultrasound frequency using sinusoidal frequency modulation. In some embodiments, the driver circuit modulates the ultrasound frequency using a linear-sweep frequency modulation. In some embodiments, the second ultrasound source is a passive planar reflector that reflects the first ultrasonic transmission. In some embodiments, the second ultrasound source is an active ultrasound source, and the driver circuit is configured to control the operation of the second ultrasound source. In some embodiments, the first ultrasound source is a phased array of ultrasonic elements. In some embodiments, the driver circuit is configured to adjust the excitations phase (i.e., time delay) between ultrasonic elements to steer a region of maximum intensity within the fluid. In some embodiments, the driver circuit is configured to control the first ultrasound source to introduce a sloshing mode to the fluid after mixing the fluid using a frequency modulated standing wave.

[0009] In another exemplary embodiment, a method for liquid mixing includes steps of a positioning, at a mixing location, a cuvette configured to hold a fluid to be mixed and providing, at the mixing location, a first ultrasound source configured to emit a first ultrasonic transmission (which can be substantially planar) substantially horizontally through a first face of a cuvette and through a fluid therein at an ultrasonic frequency. Additional steps include providing, at the mixing location, a second ultrasound source situated on an opposite side of the cuvette from the first ultrasound source that is configured to emit a second substantially planar ultrasonic transmission at the ultrasonic frequency such that the first and second substantially planar ultrasonic transmissions form a standing wave in the fluid and operating a driver circuit to control the operation of at least the first ultrasound source and to modulate the ultrasonic frequency to create a standing wave pattern of high and low pressure nodes within the fluid that changes during mixing.

[0010] In some embodiments, the step of operating a driver circuit includes modulating the ultrasound frequency with a modulation half-range of 50 kHz about the center frequency of 1.6 MHz. In some embodiments, the step of operating a driver circuit includes modulating the ultrasound frequency using sinusoidal frequency modulation. In some embodiments, the step of operating a driver circuit includes modulating the ultrasound frequency using a linear- sweep frequency modulation. In some embodiments, the second ultrasound source is a passive planar reflector that reflects the first substantially planar ultrasonic transmission. In some embodiments, the second ultrasound source is an active ultrasound source, and the driver circuit is configured to control the operation of the second ultrasound source. In some embodiments, the first ultrasound source is a phased array of ultrasonic elements. In some embodiments, the step of operating a driver circuit includes controlling the first ultrasound source to introduce a sloshing mode to the fluid after mixing the fluid using a frequency modulated standing wave.

[0011] In another exemplary embodiment, a liquid mixing system includes a motion track configured to hold and move a plurality of cuvettes that are configured to hold a fluid to be mixed, the motion track having a mixing location and an ultrasound source situated at the mixing location that is configured to emit a first substantially planar ultrasonic transmission horizontally through a first face of a first cuvette of the plurality of cuvettes and through the fluid contained therein at an ultrasonic frequency after the first cuvette is placed at the mixing location by the motion track. A reflector is situated at the mixing location on an opposite side of the first cuvette from the ultrasound source and configured to reflect the first ultrasonic transmission to create a second substantially planar ultrasonic transmission traveling toward the ultrasound source such that the first and second substantially planar ultrasonic transmissions form a standing wave in the fluid. A driver circuit is configured to control the operation of the ultrasound source and to modulate the ultrasonic frequency to create a standing wave pattern of high- and low-pressure nodes within the fluid that changes during mixing.

[0012] In some embodiments, the driver circuit modulates the ultrasound frequency with a modulation half-range of 50 kHz about the center frequency of 1.6 MHz. In some embodiments, the driver circuit modulates the ultrasound frequency using sinusoidal frequency modulation. In some embodiments, the driver circuit modulates the ultrasound frequency using a linear-sweep frequency modulation.

BRIEF DESCRIPTION OF DRAWINGS

[0013] The accompanying drawings, which are incorporated in and form a part of the specification, illustrate the embodiments of the invention and together with the written description serve to explain the principles, characteristics, and features of the invention. In the drawings:

[0014] FIG. 1 is diagrammatic sideview of an ultrasonic mixing station and exemplary cuvette for use with some illustrative embodiments;

[0015] FIG. 2 is sideview of an exemplary cuvette during a mixing phase in some illustrative embodiments;

[0016] FIGs. 3A-3E is a series of plots of the pressure distributions of ultrasonic pulse beams within an exemplary cuvette at different exemplary modulated frequencies in accordance with some illustrative embodiments;

[0017] FIGs. 4A-4E is a series of plots of the pressure distributions of ultrasonic pulse beams within an exemplary cuvette at different exemplary modulated frequencies in accordance with some illustrative embodiments;

[0018] FIG. 5 is sideview of an exemplary cuvette during a mixing phase in some illustrative embodiments; [0019] FIGs. 6A-6F of plots of the pressure distributions of ultrasonic pulse beams within an exemplary cuvette using different techniques in accordance with some illustrative embodiments;

[0020] FIG. 7 is diagrammatic block diagram of a mixing station and exemplary cuvette for use with some illustrative embodiments;

[0021] FIGs. 8a-8d are diagrammatic side views of exemplary configurations of ultrasonic sources and cuvettes for use with some illustrative embodiments;

[0022] FIG. 9 is a flow chart of an exemplary method for mixing a fluid in accordance with some illustrative embodiments.

[0023] FIG. 10 is a block diagram of an exemplary clinical chemistry system that can use concepts from some illustrative embodiments; and

[0024] FIG. 11 is a top view diagram of an exemplary clinical chemistry system that can use concepts from some illustrative embodiments.

DESCRIPTION

[0025] This disclosure is not limited to the particular systems, devices and methods described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope. [0026] As used herein, the terms “algorithm,” “system,” “module,” “engine,” or “architecture,” if used herein, are not intended to be limiting of any particular implementation for accomplishing and/or performing the actions, steps, processes, etc., attributable to and/or performed thereby. An algorithm, system, module, engine, and/or architecture may be, but is not limited to, software, hardware and/or firmware or any combination thereof that performs the specified functions including, but not limited to, any use of a general and/or specialized processor in combination with appropriate software loaded or stored in a machine-readable memory and executed by the processor. Further, any name associated with a particular algorithm, system, module, and/or engine is, unless otherwise specified, for purposes of convenience of reference and not intended to be limiting to a specific implementation. Additionally, any functionality attributed to an algorithm, system, module, engine, and/or architecture may be equally performed by multiple algorithms, systems, modules, engines, and/or architectures incorporated into and/or combined with the functionality of another algorithm, system, module, engine, and/or architecture of the same or different type, or distributed across one or more algorithms, systems, modules, engines, and/or architectures of various configurations. [0027] Embodiments disclosed herein generate non-contact mixing of reagent and sample in a reaction vessel/cuvette using ultrasonically induced bulk motion of the fluid. This is achieved using one or more ultrasonic transducers placed externally to the cuvette at an optimal lateral distance away from the cuvette. A reflecting body is placed on the other side of the fluid from the transducer to introduce a standing wave having high- and low-pressure areas. This reflecting body can be integral to the cuvette itself, a rigid body external to the cuvette, or another active transducer that operates at the same frequency as the first transducer, depending on the embodiment. In some embodiments, the reflecting surface can be the cuvette's far-side internal wall/face.

[0028] A standing wave is created by having two opposing waves (which can be substantially planar) in the fluid (the second being reflected or actively created by a transducer). Such a stationary standing wave pattern results in alternating nodal and anti- nodal regions of acoustic pressure that are spaced apart (e.g., a quarter- wavelength of the acoustic wave travelling through the mixture medium). The pressure gradients generate local bulk transport as well as diffusion-driven flows of the reaction mixture constituents. This results in some mixing of the fluids. However, in the case of a stationary (time-invariant) standing-wave pattern, the fluid mixture soon settles into an equilibrium configuration without resulting in the homogenization of the fluid mixture, in some cases. In other cases, mixing can be activated over a longer duration of time that may exceed the allocated mixing time.

[0029] To achieve full homogenization of the reaction mixture over its volume and in general, improve efficiency (e.g., reduce mix duration) of the mixing process, embodiments use spatial modulation of the standing wave pattern so that the nodal and anti-nodal pressure regions are constantly moved (oscillated) along the axis of propagation of the planar waves. This achieves a constantly varying field gradient within the fluid volume that does not allow the fluids to achieve an equilibrium configuration. The resulting bulk flow and diffusion- driven transport under this non-equilibrium field-gradient condition drives efficient mixing and achieves homogeneity across the reaction mixture volume. In addition to spatial translation of the standing wave pattern, frequency modulation (FM) also modulates the wavelength of the acoustic beam which, in turn, modulates the width of the nodal and anti- nodal regions. This further enhances the spatial modulation of the localized pressure gradients thus affording greater mixing efficacy. In the disclosed invention, the spatial modulation of the standing-wave pattern is achieved by frequency-modulation of the ultrasonic field. The nominal frequency at which the ultrasonic transducer is excited is selected based on the fundamental modal resonance of the transducer. In the case of frequency-modulation (FM), the carrier frequency f(t) is varied in a prescribed time-varying fashion. In one case, the FM could be a sinusoidal modulation wherein the carrier frequency consists of a sinusoidal low-frequency perturbation about the central frequency that would nominally line up the resonant peak of the transducer mode of operation. Another example would be a linear frequency-sweep. Other modulation types include triangular modulation, trapezoidal modulation, square-wave modulation, and randomized frequency modulation. Some embodiments combine FM with amplitude modulation (AM). One example of AM that can be helpful to prevent fluid splashing is slew-rate limiting the amplitude at the start of the mixing process. Another case of AM that can be beneficial is to pulse the input on and off at an optimal rate. This induces additional inertially-induced mixing when the fluid comes to rest when the input is turned off briefly and is agitated again when the input is turned on at the next pulse.

[0030] Considering the case of sinusoidal FM for illustration, the FM can be expressed mathematically in a simplified sense in the form of the following equation for the plane wave-front:

[0031] p(x, t)= p_0 sin (2jr(f_0+8f sin (27if_m t)+ cp(t)-kx)) Eq. (1)

[0032] Where f_m is the FM modulation frequency. In some embodiments, the FM modulation frequency is at least a couple of orders of magnitude smaller compared to the center frequency f_0, ‘k’ s the wavenumber associated with the acoustic wave, ‘x’ is the spatial variable along the direction of propagation of the acoustic waves. cp(t) is a phase and 5f is the amplitude or half-range of sinusoidal modulation of the carrier frequency.

[0033] An exemplary system for achieving standing wave acoustic mixing is shown in FIG. 1. Mixing station 10 includes cuvette 12, which holds a heterogeneous liquid 14, which requires mixing to homogenize. In some embodiments, cuvette 12 holds a 120-microliter reaction mixture volume and the reaction mixture column height is about 5 mm. In some embodiments, cuvette 12 holds between a 50-300 microliter reaction mixture volume and the reaction mixture column height is 2-15 mm. In some embodiments, successive cuvettes handled by mixing station 10 vary in fluid height as different samples include different volumes. In some embodiments, mixing station 10 is configured to handle different cuvette sizes and can change the ultrasonic beam to handle different cuvette dimensions and fluid heights (e.g.. with a priori dimension and volume data about successive samples, by configuration, or by using optical or other sensors to determine the fluid volume and cuvette dimensions). An ultrasonic beam is set incident on the face of the cuvette. In an exemplary cuvette having a rectangular horizontal cross-section, in some embodiments, this ultrasonic beam is incident on the narrower face of the cuvette such that it travels through the wider cross-sectional dimension of the cuvette. In an exemplary embodiment, the cuvette has a cross section of roughly 7mm x 3mm. In an exemplary embodiment, the cuvette has a cross section of 6-8 mm x 2-4 mm. In some embodiments, the cuvette cross section varies from 3- 15 x 20-10 mm.

[0034] Free surface 16 can be defined as the air/liquid boundary at the top of the liquid. This is differentiated between the fixed surfaces of the liquid which are bounded by the cuvette bottom and walls. A liquid to be mixed includes a heterogeneous liquid, such as two liquids placed into the cuvette via a pipette. To perform diagnostic tasks, the liquids must be homogenized via a mixing operation. The cuvette is partially submerged in a temperature- controlled bath in a reaction ring of an IVD analyzer, ty pically in a CC unit. In these examples, it is assumed that the level of the temperature-controlled bath is higher than the level of the free surface of the liquid to be mixed. The cuvette walls extend well above the free surface and the surface of the bath to prevent the temperature-controlled bath from entering the cuvette. One or more ultrasonic transducers are placed on at least one side of the cuvette, in contact with the liquid bath or in contact with a wall that contacts the liquid bath. Ultrasonic waves propagate from one or more ultrasonic transducers through the liquid bath, through the cuvette sidewall, and through the liquid to be mixed. If the ultrasonic waves are shaped in a beam, that beam impinges on the air-liquid free surface of the liquid to be mixed. We can refer to this liquid to be mixed as a reaction mixture. In some embodiments, a mixing step can include agitating or sloshing this free surface. Exemplary methods and systems for introducing a sloshing motion that can be used with some embodiments is detailed in US Patent Application 63/657,769, which is incorporated herein by its entirety. In some embodiments, FM ultrasonic mixing within the bulk fluid without large motion of the free surface is sufficient.

[0035] In embodiments that follow FM standing wave mixing with a sloshing mode, mixing by sloshing the free surface can be understood as follows. When the ultrasonic beam reaches the air-liquid interface, the air and liquid have an acoustic impedance mismatch. According to Snell's law, a beam angle below the critical angle of these two impedances will result in near-total internal reflection of the ultrasonic waves incident on the free surface. This exerts a reaction force on the free surface where the ultrasonic beam impinges. When the fluid is at rest (beginning of mixing) or relaxed (from decay after a previous pulse of the ultrasonic beam), the fluid volume proximate to this beam interaction at the free surface causes the fluid surface to deform, creating a wave on the surface. This is because of the resulting pressure differential across the air-liquid surface. This causes deformation of the free surface. Further, by applying a time-varying excitation through the ultrasonic transducer, sloshing can be induced in the fluid in a convective layer that extends down from the free surface up to a certain depth. The thickness of the convective layer depends on the sloshing amplitude, cuvette geometry⁷, and fluid properties of the reaction mixture components, mainly viscosity and density. This process is described in more detail in US Patent Application 63/657,769.

[0036] Within the water bath is an acoustic ultrasound transducer 20. This transducer can be, for example, submerged or incorporated into a wall of the bath. It may also be mounted outside the wall of the water bath, preferably without any airgaps that create an impedance mismatch. In some embodiments, transducer 20 comprises a one- or two-dimensional array of smaller ultrasonic elements 22, allowing the creation of planar beams that can be steered or focused via phase shift. This can be used to create different mixing modes, such as FM bulk mixing using substantially horizontal (within 5 degrees of horizontal) planar waves, which will be described in more detail below, followed by focusing or steering the beam at the free surface and applying pulse-width modulation or amplitude modulation (AM) to introduce a sloshing mode to more fully mix the fluid near the surface. In some embodiments, planar, standing-w ave FM modulation is sufficient, but a phased array allow s for a more flexible approach. Similarly, individual elements 22 can be turned on or off to handle different heights of surface 16 for different fluid volumes or cuvette dimensions. Further, different input voltages can be applied across the elements of the active part of the linear transducer array to help shape the field and position the beam optimally relative to the reaction fluid column in the cuvette. In an exemplary' setup, each element 22 has a 1-2 mm height, 2-4 mm width, and a 0. 1-1 mm element separation gap between them. In an exemplary setup, each element 22 has a 2-7 mm height. 5-15 mm width, and a 0. 1-2 mm element separation gap between them. In some embodiments, a single element can be used. In some embodiments, multiple elements having vary ing sizes can be used in a single array. For example, transducer 20 can include a plurality' of elements 22 that vary in height from 1 -6mm, where the taller elements are used lower, where most or all cuvettes will likely have fluid and smaller elements can be used higher up so that they can be selectively turned on match the height of the fluid. Having a larger number of elements with smaller element height and element-pitch along the vertical axis (along the height of the fluid column) can be beneficial to create uniform and planar beam characteristics (especially with focusing and beam-steering). On the other hand, larger number of elements in the array requires a larger number of independent drive channels which increases drive complexity.

[0037] Transducer 20 is placed at a distance 25 from a center of cuvette 12, such as by rotating the cuvette on circular track such that each cuvette comes to rest at the same location relative to transducer 20 within mixing station 10 each time. A reflecting source 24 (which can be a rigid reflector or an active transducer that emits in the direction opposing transducer 20) is placed at a distance 26 from the center of cuvette 12. This reflector allows a standing wave to be created within cuvette 12. In an exemplary setup, distances 25 and 26 are on the order of 5- 10mm and 3-8mm, respectively, while the overall height of transducer 20 is of the order of 10-15mm. Other dimensions are contemplated to employ these techniques to different sized cuvettes. The size of the elements, the relative location of ultrasonic sources and any reflectors, and the specific frequencies used should be chosen for the specific mixing application. The dimensions of the cuvette, the anticipated fluid height range, and the resonance frequencies relating thereto should be considered. In some embodiments, the lateral spacing of the transducer and reflector relative to the cuvette is optimally chosen to yield a substantially planar wave front and is dependent the dimensions of the elements of the array as well as the acoustic pressure intensity range that can be generated by the transducer. These parameters are optimized through a combination of simulations and design of experiments (DOE). The spacing is also chosen to minimize the impact on transducer and /or reflector tilt (pitch) due to mechanical assembly tolerances. As an example, for an array consisting of 1-2 mm tall, 2-5 mm wide elements with 0.25-1 mm inter-element spacing, a lateral spacing of 5-10 mm from the transducer to the nearest cuvette face and a lateral spacing of 5-10 mm from the reflector to its nearest-facing cuvette face is found to be the optimal range for some commercially-available cuvettes holding patient samples. Transducerarray vertical placement relative to the cuvette is a critical parameter that is optimized through a combination of simulations and DOE.

[0038] To introduce mixing, ultrasound array 20 emits an ultrasonic beam 28 across the cuvette. This is shown as curved pulses for clarity, but the beam can be described as substantially planar within the extents of transducer 20. It is understood that a perfectly planar wave is not possible in nature. Accordingly, the term “substantially planar” means that an array of ultrasound elements is operated in phase or that a single ultrasound element having dimension equal to or greater than the distance from the element to the center of the cuvette is used. In an instance where a phased array is used, we can refer to the emission as substantially planar where there is a linear phase difference between all elements such that the wave fronts create an approximate plane in the direction of the steered beam. That is. the plane is not necessarily normal to the face of an ultrasonic array and can be steered at different angles, in some embodiments. Note that while array 20 is illustrated as a 1- dimensional array for ease of depiction, this can be implemented as a 2-dimensional array for more uniform planar emission or a 1 -dimensional array with suitably sized/shaped elements. In the case of 1 -dimensional array, ultrasonic elements should be elongated in the horizontal direction to provide a substantially planar wave across the entire cuvette. It should be noted that by choosing the transducer-cuvette spacing in a suitable range (depending on the geometry of the transducer elements) the acoustic beam passing through the reaction mixture can be made “substantially planar.” In general, for a linear or 2D array, for lateral distances from the transducer elements that are substantially larger than the element dimensions, the superposition of the wavefronts emanating from the individual elements would result in a “substantially planar” wavefront, which can include local variation in the wavefront.

[0039] In some embodiments, reflecting source 24 can be another ultrasound transducer, like transducer 20. This allows the two transducers to also monitor the health of each other and to allow subsequent mixing stages that use beam steering. Steering can be achieved by introducing a phase delay between adjacent elements while health can be monitored by using one transducer (20 or 24 in this case) as an ultrasonic microphone to test the emissions of the other transducer.

[0040] Ultrasonic beam 28 traverses the water bath (the area between transducer 20 and reflecting source 24 outside cuvette 12) through the walls of cuvette 12 and exits cuvette 12 through the water bath. Reflecting source 24 provides ultrasonic emissions 29 in opposition to beam 28. Suitable reflectors for this application can include materials such as metals that have large acoustic impedance-mismatch relative to the liquid (water with additives) in the water-bath. Ultrasonic beam 28 and reflective emission 29 superpose to form a standing wave within the water bath and within cuvette 12. The standing wave comprises generally vertical components of nodal and anti-nodal pressure gradients. These pressure gradients between the nodes and anti-nodes cause advective-diffusive flow in the fluid resulting in local mixing within the bulk of fluid 14. However, a standing wave alone is not efficient at mixing the bulk of fluid 14.

[0041] To improve efficiency, ultrasonic beam 28 is frequency-modulated by transducer 20 and its driving circuit. This changes the geometry of the standing wave created by the ultrasonic beam and reflective emission. As the frequency varies, the locations (in the horizontal beam direction) of the node and anti-nodes shift, and the width of the nodal and anti-nodal regions (proportional to the wavelength of the acoustic waves) shrink and expand. [0042] FIG. 2 shows an example of what the nodes and antinodes look like in an actual fluid. Alternating nodes and anti-nodes appear as vertical bands within fluid 14. Depending on the orientation (pitch) of the ultrasonic beam and the elevation of the transducer array relative to the free surface, the ultrasonic waves can introduce some additional motion of free surface 16 within cuvette 12. This additional mob on of the free surface can be controlled by controlling the beam orientation (pitch) and by focusing the beam optimally relative to the fluid column. The additional motion of the free surface can be exploited in some cases for promoting homogenization of the fluid in the top portion of the fluid column.

[0043] FIGs. 3A-3E shows the simulated pressures of these nodes and anti-nodes as the frequency of beam 28 is varied. Whereas a wide range of FM index and modulation frequencies were found to work effectively, modulation frequency of around 10-30 Hz and a modulation half-range of 20-100 kHz is contemplated in this example. Other frequencies can be used depending on the physical dimensions being used. A selection of frequencies within this range is shown to illustrate how the standing wave pattern within the fluid changes. FIGs. 3A-3E illustrate the standing wave pattern as the frequency is modulated from a lower net frequency to a higher net frequency. Here, an ultrasound source is placed in the z direction with a reflective source on the other side. The walls of cuvette 12 is indicated by a dotted line. The standing wave pattern is notable along the horizontal x direction. Note that naturally occurring intensity roll-off in the vertical (z) direction in the beam intensity’ (from a central peak) of the substantially planar wave use in this simulation results in pressure gradients in the z direction that are less intense than those between the node and anti-nodes in the x direction. This is one reason why this example can be considered substantially planar.

[0044] Because the comparison of the different frequencies can be difficult without animation, a selected portion of these pressure nodes is illustrated in FIGs. 4A-4E focusing on the fluid portion next to the left wall of cuvette 12. (The letters of each simulation result in FIGs. 3A-3E and 4 A-4E correspond to one another for clarity.) By varying the frequency through FM modulation, the nodes and antinodes shift within the bulk of fluid 14 causing an additional mixing effect as the pressure variances are steered through the fluid. In addition, the width of the nodal and anti-nodal regions contract and expand alternatively in response to the changing ultrasonic frequency which contributes to further enhancements of the spatial gradients of the acoustic pressure field. Experimental results show that this results in efficient and complete mixing in under a second for a standard cuvette volume.

[0045] In some embodiments, FM modulation is achieved through sinusoidal frequency modulation. The sinusoidal frequency modulation can be implemented for example, using a Voltage Controlled Oscillator (VCO) w ith which a vary ing frequency of the drive signal can be achieved by providing suitably vary ing voltage input to the VCO. The FM modulation options include sinusoidal, triangular, trapezoidal, asymmetric modulation waveforms, linear frequency sweep, continuous linear frequency sweep, discrete-point frequency sweep as well as pseudo-random frequency modulation. In some embodiments, FM modulation is approximated by simply vary ing the ultrasonic frequency in a continuous or stepwise manner from a lower frequency to a higher frequency (or vice versa) during the course of mixing phase.

[0046] FIG. 5 shows the time progression of an exemplary reagent mixture being mixed using the standing wave FM modulation approach of FIGs 3A-3E. This results in complete mixing (greater than 99% homogeneity) in less than 900 milliseconds. The exact time needed to fully mix this fluid will vary depending on reagent size and fluid properties of the fluids being mixed. The total time needed to reach complete mixture can be substantially less than 900 milliseconds in some embodiments. In some embodiments, before the fluid is completely mixed, the FM modulation is stopped, and a beam steering sloshing mode is used to increase the efficiency of mixing near the free surface as explained above. An example of the sloshing mode used in this multimodal approach is explained in US patent application 63/657,769. As can be seen in the second frame of FIG. 5, initial mixing is most efficient below the free surface (nearer the boundary between components). Therefore, one efficient approach can include beginning with bulk mixing using FM modulation and finishing with sloshing mode mixing to fully incorporate fluid components near the free surface. Single or multimodal approaches can result in efficient mixing and the choice to use single or multimodal mixing can vary depending on application.

[0047] In embodiments where an additional sloshing mode step is used, by choosing different modulation parameters for an ultrasonic beam aimed incident on the free surface. different sloshing modes can be activated. In some embodiments, an asymmetric sloshing mode of the fluid is desired. By modulating the ultrasonic waves at a frequency matching or close to the resonant frequency of the asymmetric sloshing mode for the bulk fluid, rapid mixing can occur. In one sloshing mode driving scheme, the ultrasonic wave is amplitude- modulated in the form of periodic pulsing, such as a square pulse, such that the frequency of pulsing is approximately equal to the resonant frequency of the fundamental asymmetric sloshing mode.

[0048] Experiments have shown that the optimal height of the ultrasonic beam changes with different fluid heights. Thus, in some embodiments, different ultrasound elements are chosen by a processor/driver for a mixing step based on fluid properties (intrinsic and extrinsic). In some embodiments, the mechanical alignment between the fluid height and the ultrasonic transducer can also be adjusted by a processor. In some embodiments, an increased mixing time may be used to accommodate certain fluids, or a mixed mode mixing can be used. For example, multiple four-element phased sub-arrays can be used to achieve different heights if more than 3.5 mm in fluid height variation is needed. Alternatively, in some embodiments, a mechanical approach can be used to raise or lower a phased array relative to a cuvette or vice versa.

[0049] FIGs. 6A-6F illustrate the various effects of using multiple transducers 22 in ultrasound source 20. FIG. 6A shows an exemplary intensity profde in the y-z plane inside a slice of the fluid. (Note that y was previously normal to the page in FIGs. 3A-4E.) FIG. 6A shows elongated elements 22 to form an array as ultrasound source 20. Like shown FIG. 3A, the substantially-planar wavefront emitted from ultrasound source 20 is not perfectly planar. In particular, the ultrasound beam intensity experiences a roll-off from the center in the horizontal y direction. Also, because multiple elements are used with discreet gaps between them, the intensity changes due to the gaps in the z direction. In this example, the intensity profile is only shown within the fluid. Two ultrasound elements are fully above the fluid level. The acoustic pressure values here are expressed in Pascals.

[0050] FIG. 6B shows the same situation as 6A in the x-z plane, similar to FIG. 3A. This illustrates that using multiple discrete ultrasound elements results in some nonuniformities in the vertical z direction. However, these non-uniformities are substantially less than the nodeantinode behavior in the horizontal x direction. Modulation changes the location of the nodes in the x direction to facilitate mixing in that direction. But, non-uniformities in the z and y directions also create pressure differentials that can help fluid motility to aid in mixing. [0051] In some embodiments, the ultrasound beam emitted from source 20 can be steered or swept during the mixing process. For example, it is beneficial to include a mixing step that has additional intensity near the free surface, because that surface can limit mixing efficiency in the vicinity. FIG. 6C shows an exemplary intensity profile in the y-z plane, where individual ultrasound elements are operated under processor control to be selectively- activated or steered (via a phase shift between adjacent elements) to provide an additional mixing step where the most intense region is near the free surface (region 30). In this example, additional beam steering and asymmetry in the z direction is assisted by turning off element 22a. This can be done in a sweeping method or stepwise steering in a multi-step mixing process.

[0052] FIGs. 6D and 6E illustrate how the beam intensity profile in the ZX plane can be varied through beam steering of elements 22. In particular, the bottom three elements 22b are used in this simulation. In this example, for clarity-, no reflector is used (confirm), so no standing waves are shown. In FIG. 6D, the ultrasound beam is projected horizontally by operating three elements 22b in phase. In this example, it should be noted that the region of most intensity (30a) is near the bottom of the fluid. In some examples, beam steenng can be used by shifting the phase of adjacent elements within elements 22b such that the beam direction is a few degrees above horizontal. As seen in FIG. 6E, the beam has been directed roughly 3° up from the horizontal by using phase-shifting techniques. The region of most intensity (30b) is now near the center of the fluid in cuvette 12. In some embodiments, these small angular changes to steer the ultrasound beam are considered substantially horizontal because they are within 10° (and usually far less) of the horizontal plane. Beam steering can be used for many reasons, including precise tuning for different fluid volumes or to correct vertical misalignment between the cuvette and the transducer due to mechanical variation in an automation system or cuvette manufacturing. By using phased array beam steering, the central intensity of the ultrasound wave can be adjusted to compensate for such variations, under processor control.

[0053] FIG. 6F shows an alternative embodiment to the beam steering of FIG. 6E to compensate for vertical misalignment. In this example, elements 22C include an additional element (compared to the subset of elements 22b) above the fluid meniscus that can be operated to change the intensity profile within the fluid. Comparing FIG. 6E and 6F, the additional ultrasonic element helps create an intensity profile with one or more regions (30c) that are more central to mix the fluid more efficiently. Thus, a processor can selectively energize ultrasonic elements to adjust the vertical intensity profile of the ultrasound beam without necessarily using phase shifts for beam steering. FIGs. 6D-6F do not show the standing wave pattern for clarity, but the vertical intensity profile would be reflected in the standing wave pattern, as well.

[0054] In addition to selecting individual elements to form the ultrasound beam, in some embodiments, these elements can be excited in non-uniform manners to further shape and direct the beam. For example, the beam can be steered by introducing relative phase shifts between elements. The power level to each element can be adjusted to distribute the acoustic pressure more broadly or narrowly in the region of interest. Additionally, individual elements can be included or excluded in the beam, as shown.

[0055] FIG. 7 is a system diagram of mixer system 50 for use with some embodiments. Mixer system 50 includes the processing and driving elements to selectively create a pulsed ultrasonic beam and a desired incidence angle relative to the free surface of the fluid and incidence location along the fluid free surface in cuvette 60. Processor 52, in communication with memory 54 determines the appropriate characteristics for the ultrasonic beam 55. Memory 54 can include data about the fluid height and characteristics, such as viscosity and density of the reagent and sample to be mixed. This information can be provided by a laboratory information system (LIS) that tracks patient samples as they move through the IVD analyzer. Using these fluid characteristics, a lookup table or programmed routine can determine the desired characteristics of the ultrasonic beam to mix the sample and reagent given the data about the cuvette and reaction mixture. These characteristics can include frequency, intensity, modulation strategy⁷, time, height, selection of individual elements, or the like. Once processor 52 has determined the desired characteristics for the ultrasonic beam, control signals are sent to driver 56. Driver 56 applies high-frequency waveforms to appropriate piezoelectric elements in phased array 58 to create planar, FM ultrasonic emissions. In some embodiments, driver 56 can steer the beam or focus the beam with phase shifts to introduce additional selective mixing modes. Driver 56 can be any combination of circuits, such as programmable logic, analog or circuits having controllable oscillators, and the like, that allows the creation of high frequency drive signals that can be selectively applied to piezoelectric elements and modulated at a predetermined/selectable frequency.

[0056] Selecting the elements gives the elevation (vertical offset relative to cuvette bottom) of the beam source. For exemplary piezoelectric elements, a 1.6 MHz primary drive waveform is used. A high-frequency signal is modulated, such as by FM modulation, by the driver circuit 56 to achieve a modulated standing wave in the fluid.

[0057] In some embodiments, driver 56 also selectively drives an additional transducer 64 that is positioned on the other side of cuvette 60 to emit a planar emission 65 that has the same frequency characteristics as beam 55 to create and control the standing wave. In some embodiments, transducer 64 is a passive reflector such that emission 65 is a reflection of beam 55. In some embodiments, passive reflector is used and the far sidewall of cuvette 60 is used to create a reflection of beam 55. In such embodiments, cuvette 60 should have rigid walls of glass or dense plastic to increase the intensity of the natural passive reflection. To increase the intensity of the natural passive reflection from the far-side face of the cuvette, a cuvette material with significantly mismatched acoustic impedance relative to that of the fluid mixture and the fluid medium in the bath should be used.

[0058] Cuvette 60 is positioned in front of array 58 using a motion track, such as a reaction ring that rotates/translates cuvettes to mixer system 50 so that the content fluids can be homogeneously mixed before the desired reaction can be observed. While the cuvette is shown suspended alongside the phased array, it should be appreciated that it is placed and positioned via conventional mechanical automation systems (such as those shown in FIG. 11).

[0059] FIGs. 8a -8d show four different embodiments for ultrasonic mixing. In each of the embodiments disclosed in FIGs. 8a - 8d. one or more ultrasonic sources create a substantially planar wave that is emitted through the fluid. A reflector or another ultrasonic source emits another substantially planar wave through the fluid in the opposite direction at the same frequency to create a standing wave. The frequency of these ultrasonic emissions is changed, such as via FM modulation such that the geometry’ of the standing wave changes within the fluid over time during the mixing period. This creates high- and low-pressure regions to induce mixing within the fluid without substantial surface motion or sloshing. If phased arrays are used, a secondary’ sloshing mode can be introduced after the standing wave mixing.

[0060] In mixing station 80 of FIG. 8a, a single ultrasound source 20 is used to direct an ultrasonic beam horizontally' through the fluid while the opposing planar beam is generated by reflecting source 24 (which is depicted here as a passive reflector). Note that ultrasound source 20 can be a single piezoelectric element (or other ultrasonic oscillating material) or an array of several smaller piezoelectric elements. FIG. 8b shows an alternative embodiment of a mixing station 82. In mixing station 82, the ultrasonic source is broken into two smaller sources 81 and 83. Like source 20, these can be monolithic or arrays. Selecting one (or both of these) of these sources allows a processor to select the height of the planar beam to ensure the mix is effective (such as is shown in FIG. 6). In addition, the input applied to the active transducer elements in the array can be chosen optimally in such a way as to control the spatial extent of the beam in the vertical beam. The beam can thus be confined more in the region of interest spanning the height of the fluid column.

[0061] Mixing system 84 is like system 80, but the reflector has been replaced by a transducer 85 like source 20. Transducer 85 can be a monolithic emitter or an array of smaller elements. Mixing system 86 is like system 82. but the reflector has been replaced by transducers 87 and 88, which are like sources 81 and 82. Transducers 87 and 88 can be a monolithic emitter or an array of smaller elements. They can be selectively activated to select the height of the planar beam to improve mixing efficiency. It should be noted that while systems 82 and 86 show tw o vertical levels of ultrasound sources, other embodiments can use any suitable number of sources to generate planar waves. For example, three or more piezoelectric sources can be used to create a planar wave having selectable width and extents. A subset of sources can be selectively operated as a single FM source under processor control.

[0062] In some embodiments, mixing systems 84 and 86 can be operated in a diagnostic manner to detect the health/degradation of opposing ultrasound elements. During a quiescent mode of operation, each ultrasound source can be used to detect the ultrasonic radiation of the opposing source(s). That is, the quiescent transducer elements can detect ultrasonic beams reaching the elements and convert this to an electric signal. This signal can be characterized and monitored over time. This can be used to diagnose and monitor the performance/health of each phased array during the service life of the mixing mechanism. This can help detect early signs of failure of the piezoelectric elements or drive circuits before mixing efficiency is impacted. Verifying the operation of the phased arrays used for mixing can be important to avoid erroneous testing results in samples.

[0063] FIG. 9 is a flow chart of an exemplary method 100 for operating an ultrasonic mixing system, in accordance with some embodiments. At step 102, a processor receives information from the LIS regarding the fluid to be mixed. This can include cuvette dimensions, fluid volume, reagent type and physical characteristics of that reagent, such as density and viscosity, as well as any relevant intrinsic fluid characteristics of the patient sample, such as patient fluid type and an estimate of density and viscosity for such a fluid. At step 104, a reaction ring within the analyzer moves the cuvette with the fluid to be mixed to a mixing location in front of the ultrasonic elements that will perform the ultrasonic mixing steps. This step can include moving the cuvette ring and optionally confirming placement optically. This ring thereby places the cuvette in front of the ultrasound source(s) of the mixing station so that the contents can be ultrasonically mixed. At the mixing location, one ultrasound source will be at one face of the cuvette, ready to emit a beam through the cuvette face and fluid. A second source (be it a reflector or another active planar/array ultrasound source) will be placed at the opposite face to emit another beam in the opposite direction through the cuvette and fluid.

[0064] At step 106, the processor determines the ideal ultrasonic beam characteristics that will be applied to the fluid contents of the cuvette for each active ultrasound source. This includes selecting the piezoelectric elements that will be activated (such as to select the size and center height of the planar beam, as well as the modulation properties, such as frequency steps, modulation mode, etc. This can also include the intensity/amplitude of the driving signal, the frequency of the modulation, and whether an additional mixing mode (such as a sloshing mode of the ultrasonic excitation). The processor can determine these parameters using information about the volume and the intrinsic properties. At step 108, the processor provides this information to the driver circuit. At step 110, the driver circuit operates the phased array(s) to emit a beam through the side(s) of the cuvette. The driver creates driving waveforms that will be applied to the piezoelectric elements in the array(s) on the side(s) of the cuvette and, in appropriate embodiments, to any bottom transducers. This can include driving more than one phased array in embodiments such as those shown in FIGs. 8b-8d. These waveforms are then applied to the piezoelectric elements. The piezoelectric elements are then excited at the ultrasonic frequencies applied. This excitation of the piezoelectric elements is modulated by the signal in accordance with the embodiments disclosed throughout. At step 110, the driver uses the parameters received at step 108 to control the operation of the ultrasonic elements to modulate the ultrasonic transmission to mix the fluid in accordance with the signals.

[0065] At step 112, the ultrasonic beam(s) created by the piezoelectric elements reaches the fluid, provides pressure nodes within the fluid, and in turn, induces a local mixing within the bulk of the fluid via FM modulated standing waves After the modulation of the ultrasonic beam, the fluid will be completely mixed. For a cuvette having the exemplary characteristics discussed herein, experiments have shown that the fluid will be homogenized as well as if done using a mechanical impeller in under s second. Because piezoelectric elements can be excited on demand, this means that the reaction ring within the clinical chemistry portion of an IVD analyzer can move and stop very briefly before moving again. This allows very high throughput for a mixing station within the CC analy zer.

[0066] At step 114, the reaction ring of the CC analyzer rotates to move the mixed cuvette away from the mixing station and to move another cuvette into position at the mixing station. This process then repeats, with the processor controlling the operation to mix the newly placed fluid.

[0067] Clinical Chemistry Analyzer Module

[0068] One type of analyzer module in an IVD system that can benefit from the ultrasonic mixing techniques disclosed herein is a clinical chemistry module. A clinical chemistry module will be explained ith respect to a mid-volume clinical chemistry module (MVCC). A MVCC module is an instrument for performing automated clinical chemistry testing. The MVCC module can be installed as part of a larger analyzer system (e.g., analyzer 30) which might include multiple MVCC and immunoassay (IA) modules. The MVCC module can also be connected directly to a laboratory sample distribution track via a direct connect laboratory⁷ automation system (LAS) interface module. The MVCC communicates with an LIS to gather and report status of patient samples as they are processed.

[0069] The primary function of the MVCC module is to provide clinical chemistry assays using photometric and IMT detectors. An integrated multisensor technology (IMT) system uses ion selective electrodes to measure electrolytes in serum, plasma, and urine samples. An exemplary⁷ MVCC module is capable of processing a maximum of 1200 photometric assays per hour and up to 600 IMT results per hour (200 samples per hour with up to 3 electrolyte results per sample). The MVCC module includes a dilution system, an IMT (Ion Selective Electrode/ISE) system, reagent system and photometric system, and is supported via common base utilities for the MVCC module.

[0070] In some embodiments, the MVCC module has no inherent capability for loading samples and must be linked to a source/sink, such as the sample handler module or a direct load track section via the vessel mover system. The MVCC module takes one or more sample aliquots from a primary sample vessel that is positioned via the vessel mover system at an aliquot position accessible to a pipette of the MVCC module and stores them on-board for processing. [0071] The MVCC module accesses samples from an automation track (or directly at a single position on the left side, in some embodiments). The MVCC reagent cartridge design includes features which permit transfer mechanism interface and automatic cap opening; this allows it to be “automation friendly”. This allows the MVCC module to receive reagent cartridges via the automation track of the vessel mover system and automatically move these reagent cartridges from the automation track to reagent storage onboard the MVCC module. This allows the automatic delivery of reagents to the MVCC module. In some embodiments, the MVCC module can load and unload reagents to a single position on the PCM track in the back of the module (e.g., position 64 in FIG. 6) or to the manual load station in the front. [0072] FIG. 10 is a domain model of MVCC module 300. Patient samples, calibrators samples, or control samples (together, samples) 302 are sample tubes delivered via a carrier and the vessel mover system to position 56, where the sample preparation system 304 can access the sample. Sample preparation system 304 includes a pipette arm that accesses a sample access point 56. Preparation system 304 then aspirates one or more aliquots from the sample on the automation track. Based on the identity of that sample it is determined by the MVCC module whether ISE testing or photometric testing is appropriate for that sample aliquot. In the case of ISE sample testing, the aliquot is delivered to ISE sample delivery system 306. ISE sample delivery system 306 includes a plurality' of aliquot vessels, such as cuvettes, to receive the sample aliquot for ISE testing. Delivery system 306 then delivers the diluted sample aliquot to the ISE testing module that performs a standard ISE test. The resulting data of this test is then presented to module control processor 312. Processor 312 is responsible for scheduling and managing all testing going on in the MVCC module 300.

Processor 312 receives commands in test orders from an LIS or manually from an operator or test menu. Once test results are completed and presented to the processor, processor 312 reports these test results and any other status data, such as completeness of testing for that sample, to the LIS or a user interface or database.

[0073] If the sample is determined to need photometric testing, preparation system 304 presents the aliquot to the photometric sample delivery system 308. Photometric sample delivery system 308 can include a dilution ring that dilutes and stores aliquots of samples. Each photometric sample aliquot is then presented to photometric reaction system 314. This reaction system can include a reaction ring that receives samples and reagents according to a set time schedule and presents those mixed samples to photometer 316. Photometer 316 may take multiple photometric measurements of the mixed sample at a regular time interval or schedule to observe the reaction between reagents and the diluted sample. Photometer 316 then presents its findings as photometer data to module control processor 312.

[0074] Reagents can be delivered via a drawer on the front for manual delivery by an operator or by placing a reagent vessel at a predetermined location on the automation track, such as position 64. Reagent delivery system 322 receives reagents 320 from the reagent drawer or from the automation track and, using a robot arm or similar mechanical means, reagent delivery system 322 moves that reagent into a reagent storage area 324. In some embodiments, reagent delivery may require some type of preparation of that reagent by the reagent delivery system 322. Reagent storage area 324 can be an environmentally/temperature-controlled storage area where vessels of reagents are stored to be delivered as reagent aliquots on demand to the reaction ring used by the photometric reaction system 314. When a reagent is needed for a photometric test, an aliquot of that reagent can be withdrawn from reagent storage area 324 and placed into a reagent vessel or cuvettes that is part of the reaction ring of photometric reaction system 314.

[0075] MVCC module 300 also receives electricity and water from the laboratory. Water is used for cleaning and rinsing testing components to prevent cross contamination of samples or reagents. The result of testing and cleaning of equipment is liquid waste that must be evacuated by the laboratory' and treated or flushed. Consumables, such as diluent, cuvettes, or disposable tips or reagent packaging are also presented to MVCC module 300. Once these consumables are used they may be disposed by the MVCC module into a solid waste storage area (e.g., an internal trash bin), along with any empty reagent cartridges. Once full, an operator can be alerted to empty the solid waste bin and dispose of the contents appropriately (such as by placing them in the laboratory trash or biohazardous waste bin).

[0076] The MVCC module uses two measurement techniques: photometric and Ion Selective Electrode (IMT/ISE). Photometric tests are performed by mixing a sample aliquot with one or two liquid reagents and measuring light transmitted through the reaction mixture at one or more wavelengths over a period of time up to 10 minutes. IMT tests are performed by mixing a sample aliquot with IMT diluent and passing the mixture past electrodes specific to the target ions (e.g.. Na. K, and Cl).

[0077] In an exemplary embodiment, the MVCC module is capable of processing a maximum of 1,200 photometric assays per hour and up to 600 IMT results per hour (200 samples per hour with up to 3 electrolyte results per sample). All photometric and IMT assays are processed from diluted aliquots of the original sample. For photometric assays, the MVCC module prepares one or more dilutions depending on the dilution ratios of the specific tests for a sample and the amount of sample fluid needed.

[0078] For IMT assays, an aliquot of the original sample is delivered to the IMT module, which prepares the dilution internally. For IMT assays, the aliquot of original sample is added to a measured quantity of IMT diluent. The mixture is draw n through the module past the IMT chip and the voltage of each of the sensors is read. A measurement of IMT Standard A is taken immediately before or after each sample to provide reference readings.

[0079] Dilutions for photometric assays are stored on a dilution ring until needed by the MVCC test scheduling software. At the appropriate time(s) an aliquot of diluted sample is delivered into a reaction cuvette by the sample arm. In general, all photometric assays follow the same standard template: the first reagent is delivered into an empty reaction cuvette followed by sample addition and mixing. For most photometric assays a second reagent is added to the reaction mixture (and mixed) 4.3 minutes after sample addition. Photometric readings are taken at set times until the assay is complete (a maximum of 9.75 minutes). After all the photometric data has been collected the assay result is calculated using one of several available calculations.

[0080] Photometric dilution ring scheduling operates in two basic modes: Synchronous and Asynchronous. Synchronous scheduling mode is in operation when the IMT is busy or no IMT work is available. During synchronous operation photometric dilutions are being created from samples presented to the module. The dilution ring advances every 6 seconds, processing dilution cuvettes in sequence. While the dilution ring is stationary, various operations are performed around the ring, such as creating a new diluted aliquot, washing a dilution cuvette, mixing, etc. In some embodiments, each sample is transferred to up to two cuvettes on the reaction ring from a single dilution cuvette. To maintain synchronization with the reaction ring two photometric tests are scheduled for the dilution at the mix station so that w hen that dilution reaches the reaction sampling position the appropriate cuvettes are ready on the reaction ring. Any remaining tests required for the sample being scheduled (beyond two) are added to the list of pending work. If the particular dilution at the mix station has only one test requested, the second scheduled test is a generic CLEAN test.

[0081] Asynchronous scheduling mode is in operation when the IMT is idle and has work available or when the photometric pending work list gets too long or when high priority (STAT) photometric tests are available. During asynchronous operation, no new dilutions are created and no washing or mixing is performed. In asynchronous mode, the dilution ring is able to move freely as needed in order to make the highest priority photometric test available for processing.

[0082] FIG. 11 shows the hardware systems in an exemplary MVCC module 300 that may utilize the ultrasonic mixing techniques and systems disclosed herein. Samples are moved within an automated IVD system to sample access point 156 via a vessel mover system, such as patient sample tube conveyor system. Once presented, a sample may be aspirated via dilution arm 330. Dilution arm 330 is a robotic arm with a pipette configured to aspirate an aliquot of a sample. If that sample aliquot is designated by the control processor of module 300 for an ISE test, dilution arm 330 swings counterclockwise to position the pipette above and access port for IMT system 332. If the sample aliquot aspirated by dilution arm 330 is designated for photometric testing, dilution arm 330 rotates clockwise to position the pipette above dilution ring 334.

[0083] A diluter system includes dilution arm and probe 330, dilution ring 334, dilution mixer 336, and a dilution aliquot washer, along with support pumps and bulk fluid feet systems. The diluter system services the photometric system and the IMT System. The dilution arm 330 transfers the sample from the sample access point 56 on the PCM track to either the IMT System 332 or the dilution ring 334. Mixer 336 can utilize any of the structures and techniques of embodiments disclosed herein, such as mixers 50, 80, 82, 84, or 86.

[0084] For photometric assays, the dilution arm creates the necessary sample dilution(s) using saline solution. The normal dilution is 1 :5 but other dilutions are available depending upon assay requirements. An exemplary system also has the capability to perform serial dilutions (impacting throughput) at ratios up to 1:2500. The diluted sample is held for retest or reflexive testing on dilution ring 334 until that aliquot reaches the aliquot wash station. Under normal (number of tests/sample) circumstances the sample is available for greater than 10 minutes.

[0085] For the IMT assays, dilution arm 330 performs serum and/or urine dilutions directly into the IMT port where the dilution is mixed. In this case the IMT specific diluent is delivered by a separate metenng system.

[0086] IMT system 332 is responsible for testing a diluted sample using an appropriate electrode for the ISE test. Once the sample aliquot has been tested, IMT system 332 can then flush and clean the internal vessel used to test that sample portion. The results of the IMT testing are then sent to module control processor 312. IMT system 332 includes ISE module

310 from FIG. 10.

[0087] IMT system 332 processes sample (serum or urine) delivered to the IMT port by dilution arm 330. IMT diluent is metered into the entry port where it is mixed with the sample. The diluted sample is draw n into the detection electrode “stack” where the concentration of the target ions (Na, K, Cl) is measured. Reference fluid(s) can be automatically pumped into the “stack” to perform periodic calibrations. This system operates on an 18 second cycle to process 200 samples per hour for a nominal throughput of 600 assays per hour.

[0088] Dilution ring 334 includes a series of disposable or cleanable vessels/cuvettes. Once dilution ring 334 has received a sample aliquot, that ring rotates the cuvettes until each cuvette having a sample reaches the dilution mixer 336 to perform a final mix of the diluted sample, making the sample suitable for photometric testing. Dilution ring 334 continues rotating clockwise until that sample is in a position that can be accessed by sample arm 338. It should be appreciated that dilution ring 334 can act as a random-access sample ring, allowing STAT samples to be moved directly from the interaction point with dilution arm 330 dilution mixer 336 and then to a position accessible to sample arm 338.

[0089] Sample arm 338 is responsible for aspirating the dilute sample portion prepared by dilution mixer 336, moving above a reaction ring 340, and dispensing that sample portion into reaction cuvettes in that reaction ring. In some embodiments, reaction ring 340 can include a plurality of concentric rings each holding a plurality of cuvettes with samples and reagents. These rings can be moved relative to one another to allows reagents to be aspirated and dispensed into reaction vessels containing samples. In some embodiments, a single ring is used. Reagents can be added before the sample arrives or after the sample arrives via reagent arm 342 or reagent arm 344. Reagents and samples within the cuvettes in reaction ring 340 can be mixed ultrasonically using the techniques disclosed herein.

[0090] The primary' function of reagent arms 342 and 344 is to move aliquots of reagents from reagent sen' er 346 or reagent server 345, respectively. These aliquots are then dispensed into reaction vessels in reaction ring 340. In some embodiments, the vessel receiving aliquot contains a patient sample; in some embodiments the vessel is empty and the patient sample w ill be added later. Reagent servers 345 and 346 include a variety of different reagents, allowing a variety' of tests to be performed by MVCC module 300. Reaction ring 340 moves vessels in a predetermined sequence such that each reaction vessel reaches reagent mixer 348 or sample mixer 350 for mixing. Reagent mixer 348 can be used to premix reagents from reagent servers 345 and 346 or combination reagents. Sample mixer 350 is used to mix reaction vessels containing both reagent and sample. Once mixed, the reaction between the sample and reagent proceeds in the reaction vessel. Reaction ring 340 rotates to allow photometer 352 to take photometric measurements of the reaction at predetermined times. In some tests, additional reagents need to be added by reagent arms 342 and 344 at a predetermined time, the new solution mixed, and additional photometric measurements taken.

[0091] In some embodiments, the photometric system processes the photometric assays in 221 optical cuvettes on reaction ring 340. The system supports the traditional fixed assay templates used in other MVCC modules in the art. Reaction ring 340 indexes 75 cuvette positions every 3 seconds. Using this indexing pattern, a given cuvette advances 4 cuvette positions every third index. The system can initiate a new photometric test every' 3 seconds yielding a nominal throughput of 1200 assays per hour.

[0092] Assay resources include reagent- 1 delivery’, sample delivery, reagent mix-1, reagent-2 delivery and reagent mix-2 all at fixed points in time. The reactions are conducted in semi-permanent cuvettes that are washed and re-used after each assay by a cuvette washer. Assays are processed in reaction cuvettes held at constant (37° C) temperature on reaction ring 340 through the use of a heated fluid bath. The system processes assays on a 3 second cycle. [0093] The assay is initiated with addition of the first reagent (Rl) by reagent arm 344. Shortly thereafter, a precision sampler (e g. sample arm 338) transfers sample from an aliquot on the dilution ring 334 to the reaction cuvette. The contents are then mixed thoroughly with reagent mixer 348 or sample mixer 350 and a reaction ensues. The reaction cuvette is read by photometer 352 approximately once every 9 seconds while reaction ring 340 is indexing. The photometer 352 a standard set of 11 wavelengths currently used by similar photometers in the art. Photometer 352 supports absorbance and turbidimetric assays using the 11 available wavelengths.

[0094] Some assays only require a single reagent while others require a second reagent addition. The second reagent is added by reagent arm 342 at a fixed point in time (e.g., approximately 260 seconds after sample addition) and the reaction is mixed by reagent mixer 348 or sample mixer 350. The reaction is read by the photometer as before.

[0095] Reagent servers 346 and 345 contain a series of radially oriented reagent vessels placed in two concentric rings. These reagent vessels can be loaded via reagent loader 354. Reagent loader 354 includes a robot arm that moves on a gantry' that allows it to be positioned above the vessel mover access point 64 on the automation track. The mechanical components of the reagent loader 354 can be substantially the same as those discussed with respect to robot arm 20, configured to interact with reagent cartridges. When a reagent within reagent server 345 or 346 needs to be refilled, the servers will automatically eject the empty cartridge, and the vessel mover system will retrieve a replacement reagent cartridge and position that cartridge via a carrier at the vessel mover access point 64. Reagent loader 354 will then move to that position and pick up the reagent cartridge using end effectors. Reagent loader 354 will then move that reagent cartridge to the appropriate empty slot in reagent server 345 or 346 and insert the cartridge into that location in the reagent server. [0096] Alternatively, an operator can manually load reagents at the request of the machine or at a predetermined schedule. The operator can load a series of reagent cartridges into a tray at reagent manual load station 356. Reagent manual load station 356 includes a linear slide that receives the tray and moves the tray into position underneath reagent loader 354. End effectors of the robot arm of the reagent loader can then remove reagent cartridges from the tray place at the reagent manual load station 356 and move those cartridges into the appropriate slot in the reagent servers. This allows automatic or manual loading of reagents. [0097] Reagents are stored and provided by the reagent system. The reagent system includes two refrigerated rotary reagent servers. One server (345) is dedicated solely to the first reagent addition and one (346) to the second reagent addition. Each server operates on a 3 second cycle with about 1 second allocated for motion and 2 seconds allocated for access by the respective reagent arms. Each reagent server holds reagent cartridges arranged in two concentric rings. There are 24 cartridges on the inner ring and 46 cartridges on the outer for a total cartridge capacity of 70. In some embodiments, up to four positions on each server can be dedicated to cartridges holding special cleaning fluids and one position can be held open for loading and unloading logistics. This means an exemplary system can simultaneously support 65 different on-board assays.

[0098] Reagent cartridges are loaded into the servers by reagent loader 354. Reagent loader 354 presents the reagent cartridge to a barcode reader to confirm the identity of the cartridge (PCM track load at position 64) or to identity the cartridge (reagent manual load station 356). Reagent loader 354 then places the cartridge in the appropriate server position (in server 345 or 346). [0099] The reagent cartridge is sized for ease of handling by the PCM and has gripping features to allow pickup using reagent loader 354 and a PCM reagent handler (e.g. robot arm 20). The cartridge is closed with a screw-on cap with auto-open features. One or more bar- coded labels are provided for identification by the customer and the system. The cartridge has dual wells with 25 ml capacity in each well. The dual well configuration can allow for longer on-board stability by only opening each well as needed.

[0100] The reagent cartridge is closed with a screw-on cap that can be opened either by the customer (in the case of the need for pre-hydrating the reagent) or automatically by the system. This cap should maintain a hermetic seal for long-term storage but be easily opened in use. This closure system is auto-open only with no provision to re-seal the opened cap. A foil seal is designed for piercing by reagent loader 354.

[0101] The embodiments of the present disclosure may be implemented with any combination of hardware and software. In addition, the embodiments of the present disclosure may be included in an article of manufacture (e.g., one or more computer program products) having, for example, computer-readable, non-transitory media. The media has embodied therein, for instance, computer readable program code for providing and facilitating the mechanisms of the embodiments of the present disclosure. The article of manufacture can be included as part of a computer system or sold separately.

[0102] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

[0103] An executable application, as used herein, comprises code or machine-readable instructions for conditioning the processor to implement predetermined functions, such as those of an operating system, a context data acquisition system or other information processing system, for example, in response to user command or input. An executable procedure is a segment of code or machine-readable instruction, sub-routine, or other distinct section of code or portion of an executable application for performing one or more particular processes. These processes may include receiving input data and/or parameters, performing operations on received input data and/or performing functions in response to received input parameters, and providing resulting output data and/or parameters.

[0104] A graphical user interface (GUI), as used herein, comprises one or more display images, generated by a display processor and enabling user interaction with a processor or other device and associated data acquisition and processing functions. The GUI also includes an executable procedure or executable application. The executable procedure or executable application conditions the display processor to generate signals representing the GUI display images. These signals are supplied to a display device which displays the image for viewing by the user. The processor, under control of an executable procedure or executable application, manipulates the GUI display images in response to signals received from the input devices. In this way, the user may interact with the display image using the input devices, enabling user interaction with the processor or other device.

[0105] The functions and process steps herein may be performed automatically or wholly or partially in response to user command. An activity (including a step) performed automatically is performed in response to one or more executable instructions or device operation without user direct initiation of the activity.

[0106] While various illustrative embodiments incorporating the principles of the present teachings have been disclosed, the present teachings are not limited to the disclosed embodiments. Instead, this application is intended to cover any variations, uses, or adaptations of the present teachings and use its general principles. Further, this application is intended to cover such departures from the present disclosure that are within known or customary⁷ practice in the art to which these teachings pertain.

[0107] In the above detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the present disclosure are not meant to be limiting. Other embodiments may be used, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that various features of the present disclosure, as generally described herein, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of w hich are explicitly contemplated herein.

[0108] Aspects of the present technical solutions are described herein with reference to flowchart illustrations and/or block diagrams of methods, apparatuses (systems), and computer program products according to embodiments of the technical solutions. It will be understood that each block of the flow chart illustrations and/or block diagrams, and combinations of blocks in the flow chart illustrations and/or block diagrams, can be implemented by computer readable program instructions. [0109] These computer readable program instructions can be provided to a processor of a general-purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks. These computer readable program instructions can also be stored in a computer readable storage medium that can direct a computer, a programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having instructions stored therein comprises an article of manufacture including instructions which implement aspects of the function/act specified in the flowchart and/or block diagram block or blocks.

[0110] The computer readable program instructions can also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.

[OHl] The flowchart and block diagrams in the figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the present technical solutions. In this regard, each block in the flowchart or block diagrams can represent a module, segment, or portion of instructions, which includes one or more executable instructions for implementing the specified logical function(s). In some alternative implementations, the functions noted in the blocks can occur out of the order noted in the figures. For example, two blocks shown in succession can, in fact, be executed substantially concurrently, or the blocks can sometimes be executed in the reverse order, depending upon the functionality involved. It will also be noted that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware-based systems that perform the specified functions or acts or carry out combinations of special purpose hardware and computer instructions.

[0112] A second action can be said to be “in response to” a first action independent of whether the second action results directly or indirectly from the first action. The second action can occur at a substantially later time than the first action and still be in response to the first action. Similarly, the second action can be said to be in response to the first action even if intervening actions take place between the first action and the second action, and even if one or more of the intervening actions directly cause the second action to be performed. For example, a second action can be in response to a first action if the first action sets a flag and a third action later initiates the second action whenever the flag is set.

[0113] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various features. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, compositions or biological systems, which can, 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.

[0114] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity.

[0115] It will be understood by those within the art that, in general, terms used herein are generally intended as “open’’ terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” et cetera). While various compositions, methods, and devices are described in terms of “comprising” various components or steps (interpreted as meaning “including, but not limited to”), the compositions, methods, and devices can also “consist essentially of’ or “consist of’ the various components and steps, and such terminology should be interpreted as defining essentially closed-member groups.

[0116] As used in this document, the singular forms “a.” “an.” and “the” include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention.

[0117] In addition, even if a specific number is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B. and C, et cetera” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B. and C together, et cetera). In those instances where a convention analogous to “at least one of A, B, or C, et cetera” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a sy stem having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together. B and C together, and/or A, B. and C together, et cetera). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, sample embodiments, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0118] In addition, where features of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0119] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily- recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, et cetera. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, et cetera. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges that can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 components refers to groups having 1, 2, or 3 components. Similarly, a group having 1-5 components refers to groups having 1, 2, 3, 4, or 5 components, and so forth.

[0120] Independent of the grammatical term usage, individuals with male, female or other gender identities are included within the term. Various of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications. Various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art, each of which is also intended to be encompassed by the disclosed embodiments.

NON-LIMITING ILLUSTRATIVE EMBODIMENTS

[0121] The following is a list of non-limiting illustrative embodiments disclosed herein: [0122] Illustrative embodiment 1. A liquid mixing system comprising a cuvette configured to hold a fluid to be mixed; a first ultrasound source situated on one side of the cuvette and configured to emit a first substantially planar ultrasonic transmission horizontally through a first face of the cuvette through the fluid at an ultrasonic frequency; a second ultrasound source situated on an opposite side of the cuvette and configured to emit a second substantially planar ultrasonic transmission at the ultrasonic frequency such that the first and second substantially planar ultrasonic transmissions form a standing wave in the fluid; a driver circuit configured to control the operation of at least the first ultrasound source and to modulate the ultrasonic frequency to create a standing wave pattern of high and low pressure nodes within the fluid that changes during mixing.

[0123] Illustrative embodiment 2. The liquid mixing system of one of the preceding illustrative embodiments, wherein the first ultrasound source comprises a phased array of ultrasonic elements.

[0124] Illustrative embodiment 3. The liquid mixing system of one of the preceding illustrative embodiments, wherein the driver circuit is configured to adjust a phase of excitation between ultrasonic elements to steer a region of maximum intensity within the fluid.

[0125] Illustrative embodiment 4. The liquid mixing system of one of the preceding illustrative embodiments, wherein the first ultrasound source comprises a phased array of ultrasonic elements. [0126] Illustrative embodiment 5. The liquid mixing system of one of the preceding illustrative embodiments wherein the driver circuit modulates the ultrasound frequency using a linear-sweep frequency modulation.

[0127] Illustrative embodiment 6. The liquid mixing system of one of the preceding illustrative embodiments wherein the second ultrasound source comprises a passive planar reflector that reflects the first substantially planar ultrasonic transmission.

[0128] Illustrative embodiment 7. The liquid mixing system of one of the preceding illustrative embodiments, wherein the second ultrasound source comprises an active ultrasound source, and the driver circuit is configured to control the operation of the second ultrasound source.

[0129] Illustrative embodiment 8. The liquid mixing system of one of the preceding illustrative embodiments, wherein the driver circuit is configured to control the first ultrasound source to introduce a sloshing mode to the fluid after mixing the fluid using a frequency modulated standing wave.

[0130] Illustrative embodiment 9. A method for liquid mixing comprising positioning, at a mixing location, a cuvette configured to hold a fluid to be mixed; providing, at the mixing location, a first ultrasound source configured to emit a first substantially planar ultrasonic transmission horizontally through a first face of a cuvette and through a fluid therein at an ultrasonic frequency; providing, at the mixing location, a second ultrasound source situated on an opposite side of the cuvette from the first ultrasound source that is configured to emit a second substantially planar ultrasonic transmission at the ultrasonic frequency such that the first and second substantially planar ultrasonic transmissions form a standing wave in the fluid; and operating a driver circuit to control the operation of at least the first ultrasound source and to modulate the ultrasonic frequency to create a standing wave pattern of high and low pressure nodes within the fluid that changes during mixing.

[0131] Illustrative embodiment 10. The method for liquid mixing of one of the preceding illustrative embodiments starting with embodiment 9, wherein the first ultrasound source comprises a phased array of ultrasonic elements.

[0132] Illustrative embodiment 11. The method for liquid mixing of one of the preceding illustrative embodiments, wherein the driver circuit is configured to adjust a phase of excitation between ultrasonic elements to steer a region of maximum intensity within the fluid. [0133] Illustrative embodiment 12. The method for liquid mixing of one of the preceding illustrative embodiments starting with embodiment 9. wherein the step of operating a driver circuit comprises modulating the ultrasound frequency using sinusoidal frequency modulation.

[0134] Illustrative embodiment 13. The method for liquid mixing of one of the preceding illustrative embodiments starting with embodiment 9, wherein the step of operating a driver circuit comprises modulating the ultrasound frequency using a linear-sweep frequency modulation.

[0135] Illustrative embodiment 14. The method for liquid mixing of one of the preceding illustrative embodiments starting with embodiment 9, wherein the second ultrasound source comprises a passive planar reflector that reflects the first substantially planar ultrasonic transmission.

[0136] Illustrative embodiment 15. The method for liquid mixing of one of the preceding illustrative embodiments starting with embodiment 9, wherein the step of operating a driver circuit comprises controlling the first ultrasound source to introduce a sloshing mode to the fluid after mixing the fluid using a frequency modulated standing wave.

[0137] Illustrative embodiment 16. The method for liquid mixing of one of the preceding illustrative embodiments starting with embodiment 9, wherein the step of operating a driver circuit comprises controlling the first ultrasound source to introduce a sloshing mode to the fluid after mixing the fluid using a frequency modulated standing wave.

[0138] Illustrative embodiment 17. A liquid mixing system comprising a motion track configured to hold and move a plurality of cuvettes that are configured to hold a fluid to be mixed, the motion track having a mixing location: an ultrasound source situated at the mixing location that is configured to emit a first substantially planar ultrasonic transmission horizontally through a first face of a first cuvette of the plurality of cuvettes and through the fluid contained therein at an ultrasonic frequency after the first cuvette is placed at the mixing location by the motion track; a reflector situated at the mixing location on an opposite side of the first cuvette from the ultrasound source and configured to reflect the first ultrasonic transmission to create a second substantially planar ultrasonic transmission traveling toward the ultrasound source such that the first and second substantially planar ultrasonic transmissions form a standing wave in the fluid; a driver circuit configured to control the operation of the ultrasound source and to modulate the ultrasonic frequency to create a standing wave patern of high and low pressure nodes within the fluid that changes during mixing.

[0139] Illustrative embodiment 18. The liquid mixing system of one of illustrative embodiment 17, wherein the first ultrasound source comprises a phased array of ultrasonic elements.

[0140] Illustrative embodiment 19. The liquid mixing system of one of the preceding illustrative embodiments starting with 17, wherein the driver circuit modulates the ultrasound frequency using sinusoidal frequency modulation.

[0141] Illustrative embodiment 20. The liquid mixing system of one of the preceding illustrative embodiments starting with 17, wherein the driver circuit modulates the ultrasound frequency using a linear-sweep frequency modulation.

Claims

CLAIMS We claim:

1 . A liquid mixing system comprising: a cuvette configured to hold a fluid to be mixed; a first ultrasound source situated on one side of the cuvette and configured to emit a first ultrasonic transmission horizontally through a first face of the cuvette through the fluid at an ultrasonic frequency; a second ultrasound source situated on an opposite side of the cuvette and configured to emit a second ultrasonic transmission at the ultrasonic frequency such that the first and second ultrasonic transmissions form a standing wave in the fluid; a driver circuit configured to control the operation of at least the first ultrasound source and to modulate the ultrasonic frequency to create a standing wave pattern of high- and low-pressure nodes within the fluid that changes during mixing.

2. The liquid mixing system of claim 1, wherein the first ultrasound source comprises a phased array of ultrasonic elements.

3. The liquid mixing system of claim 2, wherein the driver circuit is configured to adjust a phase of excitation between ultrasonic elements to steer a region of maximum intensity within the fluid.

4. The liquid mixing system of claim 1, wherein the driver circuit modulates the ultrasound frequency using sinusoidal frequency modulation.

5. The liquid mixing system of claim 1, wherein the driver circuit modulates the ultrasound frequency using a linear-sweep frequency modulation.

6. The liquid mixing system of claim 1, wherein the second ultrasound source comprises a passive planar reflector that reflects the first ultrasonic transmission.

7. The liquid mixing system of claim 1, wherein the second ultrasound source comprises an active ultrasound source, and the driver circuit is configured to control the operation of the second ultrasound source.

8. The liquid mixing system of claim 2, wherein the driver circuit is configured to control the first ultrasound source to introduce a sloshing mode to the fluid after mixing the fluid using a frequency modulated standing wave.

9. A method for liquid mixing comprising: positioning, at a mixing location, a cuvette configured to hold a fluid to be mixed; providing, at the mixing location, a first ultrasound source configured to emit a first ultrasonic transmission horizontally through a first face of a cuvette and through a fluid therein at an ultrasonic frequency; providing, at the mixing location, a second ultrasound source situated on an opposite side of the cuvette from the first ultrasound source that is configured to emit a second ultrasonic transmission at the ultrasonic frequency such that the first and second ultrasonic transmissions form a standing wave in the fluid; and operating a driver circuit to control the operation of at least the first ultrasound source and to modulate the ultrasonic frequency to create a standing wave pattern of high and low pressure nodes within the fluid that changes during mixing.

10. The method of claim 9, wherein the first ultrasound source comprises a phased array of ultrasonic elements.

1 1. The method of claim 9, wherein the step of operating a driver circuit comprises adjusting a phase of excitation between ultrasonic elements to steer a region of maximum intensity within the fluid.

12. The method of claim 9, wherein the step of operating a driver circuit comprises modulating the ultrasound frequency using sinusoidal frequency modulation.

13. The method of claim 9, wherein the step of operating a driver circuit comprises modulating the ultrasound frequency using a linear-sweep frequency modulation.

14. The method of claim 9, wherein the second ultrasound source comprises a passive planar reflector that reflects the first ultrasonic transmission.

15. The method of claim 9, wherein the second ultrasound source comprises an active ultrasound source, and the driver circuit is configured to control the operation of the second ultrasound source.

16. The method of claim 9, wherein the step of operating a driver circuit comprises controlling the first ultrasound source to introduce a sloshing mode to the fluid after mixing the fluid using a frequency modulated standing wave.

17. A liquid mixing system comprising: a motion track configured to hold and move a plurality of cuvettes that are configured to hold a fluid to be mixed, the motion track having a mixing location; an ultrasound source situated at the mixing location that is configured to emit a first ultrasonic transmission horizontally through a first face of a first cuvette of the plurality of cuvettes and through the fluid contained therein at an ultrasonic frequency after the first cuvette is placed at the mixing location by the motion track; a reflector situated at the mixing location on an opposite side of the first cuvette from the ultrasound source and configured to reflect the first ultrasonic transmission to create a second ultrasonic transmission traveling toward the ultrasound source such that the first and second ultrasonic transmissions form a standing wave in the fluid; a driver circuit configured to control the operation of the ultrasound source and to modulate the ultrasonic frequency to create a standing wave pattern of high and low pressure nodes within the fluid that changes during mixing.

18. The liquid mixing system of claim 17. wherein the first ultrasound source comprises a phased array of ultrasonic elements.

19. The liquid mixing system of claim 17, wherein the driver circuit is configured to adjust a phase between ultrasonic elements to steer a region of maximum intensity within the fluid.

20. The liquid mixing system of claim 17, wherein the driver circuit modulates the ultrasound frequency using frequency modulation.