Mixing of reagent and sample using ultrasonic excitation of sloshing mode

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 one phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a first ultrasonic transmission through a first face of the cuvette at an upward angle that creates a beam that intersects the free surface of the fluid to induce a sloshing mode. A dnver circuit is configured to control the operation of the ultrasonic elements and to modulate the first ultrasonic transmission substantially at or near a resonant frequency of the fluid.

Description

MIXING OF REAGENT AND SAMPLE USING ULTRASONIC EXCITATION OF SLOSHING MODE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of US Provisional Patent Application Serial No.63 / 657,769, filed on June 7, 2024, which is incorporated by reference herein in its entirety. BACKGROUND

[0002] 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).

[0003] 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 downward angle, away from the free surface of the fluid to help create motion in the fluid. These prior examples do not mention controlling attributes of the ultrasonic waves based on the resonant properties of the fluid being mixed. Accordingly, there remains room for improvement in ultrasonic mixing for IVD tasks.  SUMMARY

[0004] Disclosed mixing methods and systems use ultrasonic energy in a non-contact method that mitigates carryover and contamination risks. 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.

[0005] In an exemplary embodiment, a liquid mixing system comprises a cuvette configured to hold a fluid to be mixed and a first phased array of ultrasonic elements oriented in a substantially vertical array. The first phased array is configured to emit a first ultrasonic transmission through a first face of the cuvette at an upward angle that is within a range of beam-incidence of 3 to 30 degrees such that it generally intersects the free surface. A driver circuit is configured to control the operation of the ultrasonic elements and to modulate the first ultrasonic transmission substantially at or near an asymmetric sloshing mode resonant frequency of the fluid.

[0006] In some embodiments, the phased array is concave, while on others it is planar. some embodiments, the driver circuit modulates the first ultrasonic transmission at a rate that is substantially at a frequency defined by sqrt((g / 2 / pi)*(tanh(pi*h / l)) / l), where g is gravity, h is fluid height, and l is the length of the cuvette in the direction of the first ultrasonic transmission. In some embodiments, a processor is configured to select modulation properties of the first ultrasonic transmission based on at least a volume of the fluid. In some embodiments, a processor is configured to select modulation properties of the first ultrasonic transmission based on at least a type of the fluid, a viscosity of the fluid, a density of the fluid, or other intrinsic properties of the fluid. In some embodiments, a processor is configured to select modulation properties comprising excitation amplitude, modulation frequency, pulse-type, and pulse duty-cycle such that the fluid is mixed in a stable sloshing regime. This pulse type can include, for example, square pulses, sinusoidal pulses, trapezoidal pulses, or triangular pulses.

[0007] In some embodiments, a second phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a second ultrasonic transmission through a second face of the cuvette, opposite to the first face. In some embodiments, the driver circuitis configured to pulse the second phased array out of phase with the first phased array at the resonant frequency of the fluid. In some embodiments, a bottom ultrasonic transducer is placed below the cuvette and configured to emit a second ultrasonic transmission through the bottom of the cuvette towards the free surface of the fluid, substantially modulated at the resonant frequency. In some embodiments, the bottom ultrasonic transducer is operated out of phase with the first phased array such that a substantial part of a pulse by the bottom ultrasonic transducer occurs between pulses by the first phased array.

[0008] In another exemplary embodiment, a method of operating a liquid mixing system comprises placing a cuvette holding a fluid to be mixed in front of a first phased array of ultrasonic elements oriented in a substantially vertical array and operating the first phased array to emit a first ultrasonic transmission through a first face of the cuvette at an upward angle that is within a range of beam-incidence of 3 to 30 degrees using beam steering. Steps further include controlling the operation of the ultrasonic elements and to modulate the first ultrasonic transmission substantially at or near a fundamental asymmetric sloshing mode resonant frequency of the fluid.

[0009] In some embodiments, steps include selecting, using a processor, modulation properties of the first ultrasonic transmission based on at least a volume of the fluid. In some embodiments, steps include selecting, using a processor, modulation properties of the first ultrasonic transmission based on at least one intrinsic property of the fluid. In some embodiments, steps include selecting, using a processor, modulation properties comprising excitation amplitude, modulation frequency, pulse type, and pulse duty-cycle such that the fluid is mixed in a stable sloshing regime. In some embodiments, steps include operating a second phased array of ultrasonic elements oriented in a substantially vertical array to emit a second ultrasonic transmission through a second face of the cuvette, opposite to the first face. In some embodiments, steps include pulsing the second phased array out of phase with the first phased array at the fundamental asymmetric sloshing-mode resonant frequency of the fluid. In some embodiments, the pulsing can be slew-rate limited (to prevent issues such as violent excitation of the fluid surface resulting in splashing or droplet ejection). In some embodiments, the pulse can be shaped in the form of a half-sinusoid. In other embodiments, the pulse can assume a triangular or trapezoidal waveform. In some embodiments, steps include operating a bottom ultrasonic transducer placed below the cuvette to emit a second ultrasonic transmission through the bottom of the cuvette towards the free surface of thefluid, substantially modulated at the fundamental asymmetric sloshing-mode resonant frequency.

[0010] In another exemplary embodiment, a liquid mixing system comprises a reaction ring configured to hold and move a plurality of reaction vessels containing fluid comprising a patient sample and reagent to be mixed and a first phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a first ultrasonic transmission through a first face of each reaction vessel when the vessel is placed by the reaction ring at a position proximate to the first phased array at an upward angle such that the first ultrasonic transmission intersects a free surface of the fluid. A driver circuit is configured to control the operation of the ultrasonic elements and to modulate the first ultrasonic transmission substantially at or near a fundamental asymmetric sloshing-mode resonant frequency of the fluid.

[0011] In some embodiments, a second phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a second ultrasonic transmission through a second face of each reaction vessel opposite to the first face. In some embodiments, a bottom ultrasonic transducer placed below the reaction vessel and configured to emit a second ultrasonic transmission through the bottom of the reaction vessel towards the free surface of the fluid, substantially modulated at the sloshing mode resonant frequency. In some embodiments, a processor is configured to select modulation properties comprising excitation amplitude, modulation frequency, pulse type and pulse duty-cycle such that the fluid is mixed in a stable-swirl mode sloshing regime. In some embodiments, the upward angle is within a range of beam-incidence of 3 to 30 degrees relative to horizontal. In some embodiments, the second phased array monitors the performance of the first phased array. BRIEF DESCRIPTION OF DRAWINGS

[0012] 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:

[0013] FIG.1 is plot of pulse frequencies and sloshing modes for an exemplary cuvette for use with some illustrative embodiments;

[0014] FIG.2 is plot of pulse frequencies and fluid height to achieve a desired sloshing mode for an exemplary cuvette for use with some illustrative embodiments;

[0015] FIG.3 is plot of normalized pulse frequencies and different sloshing regimes for different excitation amplitudes for an exemplary cuvette for use with some illustrative embodiments;

[0016] FIG.4 is diagrammatic sideview of a phased array and exemplary cuvette for use with some illustrative embodiments;

[0017] FIG.5 is a series of plots of the pressure distributions of ultrasonic pulse beams within an exemplary cuvette at different exemplary conditions for use with some illustrative embodiments;

[0018] FIG.6 is diagrammatic block diagram of a phased array(s) and exemplary cuvette for use with some illustrative embodiments;

[0019] FIG.7 is an exemplary pulse timing diagram for use with some illustrative embodiments;

[0020] FIGs.8a-8h are diagrammatic side views of exemplary configurations of phased arrays and cuvettes for use with some illustrative embodiments;

[0021] FIG.9 is a flow chart of an exemplary method for mixing a fluid in accordance with some illustrative embodiments.

[0022] FIG.10 is a block diagram of an exemplary clinical chemistry system that can use concepts from some illustrative embodiments; and

[0023] FIG.11 is a top view diagram of an exemplary clinical chemistry system that can use concepts from some illustrative embodiments. DESCRIPTION

[0024] 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.

[0025] 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 ofconvenience 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.

[0026] Embodiments disclosed herein generate non-contact mixing of reagent and sample in a reaction vessel / cuvette using ultrasonically inducing bulk motion of the fluid. This is achieved using one or more ultrasonic transducers placed external to the cuvette at an optimal lateral distance away from the cuvette. The vertical placement and orientation of the ultrasonic source is such that the ultrasonic beam is directed upwards at an angle towards the free surface of the fluid mixture in the cuvette. Sloshing can be induced in the case of the beam directed downwards at the free surface of the fluid mixture. However, the beam would pass through the air above the free surface resulting in significant losses due to impedance mismatch between the cuvette material and air. Thus, while embodiments can achieve mixing by directing the beam downwards, it is desirable to use an ultrasound beam that originated below the free surface height.

[0027] The free surface 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, typically 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 the 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. When the ultrasonicbeam 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 geometry, and fluid properties of the reaction mixture components, mainly viscosity and density.

[0028] By choosing different modulation parameters for this ultrasonic beam 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.

[0029] In one 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. For an exemplary case of a 120-microliter reaction mixture volume in a typical clinical chemistry cuvette, the reaction mixture column height is about 5.2 mm. 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 7 mm x 3 mm. In an exemplary embodiment, the cuvette has a cross section of 5-1 mm x 2-6 mm.

[0030] For a cuvette having these dimensions, one can calculate approximate sloshing modal frequencies. FIG.1 shows exemplary sloshing modal frequencies for such a cuvette. In some embodiments, mode (1, 0) is desirable. This results in a fundamental asymmetric sloshing mode that allows the free surface to roll onto itself. In this case, for an exemplary cuvette used in a one commercial clinical chemistry analyzer, this frequency was found to be14-15 Hertz. When an ultrasonic beam is incident on the free surface at an angle and driven at or near 14-15 Hz, the asymmetric (1,0) sloshing mode is excited and the mixture can be successfully and quickly mixed. FIG.1 shows the sloshing modes for a fluid column height of around 5 mm. The fluid height affects the resonant properties of the fluid. However, as shown in FIG.2, the fundamental frequencies for different heights are quite similar for a given cuvette geometry. For example, the difference between a fluid column height of 5 mm and 11 mm is on the order of 0.5 Hertz. As the fluid column height changes, it can be seen that an asymptote occurs just over 14.6 hertz. For different cuvette dimensions, the resonant frequencies will be different from this example and the optimal frequency for achieving sloshing mode mixing should be selected accordingly.

[0031] In the simplest embodiment, the driving waveform for the ultrasonic beam is square wave amplitude modulation. Pulsing the ultrasound beam at a frequency in the range of 14-15 Hertz excites the fundamental asymmetric sloshing mode for the reaction mixture fluid. Meanwhile, the on / off times (duty cycle) of the pulsing, the pulse type (such as sinusoidal or trapezoidal / square pulse) and the amplitude can be chosen based on different factors. In some embodiments, other forms of modulation of the ultrasonic wave amplitude besides square wave pulsing can be used. For example, sinusoidal, saw-tooth, and trapezoidal amplitude modulation waveforms can be used. The modulation frequency for these schemes should be at or near the resonant frequency of the fundamental asymmetric sloshing mode. Sloshing mode frequency (f_ij) calculations can be simplified for a cuvette with rectangular cross-section: f_ij = sqrt((g / 2 / pi)*(kappa*tanh(pi*h*kappa))); kappa = sqrt((i / l_cuv)^2 + (j / w_cuv)^2); where i and j represent the nodal indices of the two cross- sectional dimensions of the cuvette, respectively. l_cuv and w_cuv are the width and depth of the cuvette, h is the height of the fluid column and g is gravity (9.81 m / s^2). (These dimensions are illustrated in FIG.8a.) While this explains the resonant frequency for a rectangular cuvette, other geometries can also be used. The sloshing resonant frequency can be computed for a given cuvette geometry and fill height, and the ultrasonic beam can be amplitude-modulated or pulsed at or near that frequency.

[0032] For example, to excite a desirable asymmetric sloshing mode, (i, j) will be (1,0). Thus kappa becomes 1 / l_cuv and f_1,0 = sqrt((g / 2 / pi)*(tanh(pi*h / l_cuv)) / l_cuv). For an exemplary 7 mm x 3 mm cuvette with a fluid height of 5 mm a fundamental asymmetric sloshing mode along the 7 mm dimension occurs at 14.6 Hz. An embodiment is said to have a modulation frequency substantially defined by f_i,j if it is modulated at a frequency within15% of this defined formula. It is preferred that the asymmetric sloshing mode be (1,0), where the ultrasonic transducers are aligned so that pulses generally go in the direction of l_cuv. Embodiments seek to achieve a beam that is modulated at the frequency f_ij (where ij is 1,0). This can be referred to as the first resonance frequency of sloshing for the vessel. Embodiments seek to achieve f_1,0 + / - 10% during missing operation.

[0033] Because the variation in fundamental sloshing mode frequency does not vary greatly for different fluid column heights, a single frequency for exciting the free surface can be used, in some embodiments. There, a single frequency can be used for all fluid volumes. In other embodiments, the pulse frequency can be selected from a lookup table by a processor based on a priori knowledge of the fluid volume of the reaction mixture in the cuvette. In some embodiments, a processor can take information about the fluid properties and cuvette geometry and run a calculation to determine an approximate ideal resonant frequency and duty cycle using any of the calculations disclosed herein. These approaches allow the pulse frequency for the ultrasonic beam to be tailored to the fluid volume, cuvette geometry as well as the fluid types (having different intrinsic properties, mainly viscosity and density) to enable more efficient mixing at the fundamental sloshing mode frequency for that volume.

[0034] It should be appreciated that sideways sloshing of the fluid is unlike other ultrasonic mixing methods disclosed in prior art. Sideways sloshing has twofold benefits. First, the periodic sloshing motion allows excitation at a large enough amplitude to generate a largely stable swirling motion at the free surface. This then generates internal circulation within the interior volume of the reaction mixture which results in efficient bulk mixing. Second, the periodic sloshing motion of the fluid causes shearing between layers of the fluid that enhances mixing across the layers, resulting in more efficient mixing.

[0035] The nature of the sloshing response for sideways sloshing induced by ultrasonic excitation is a function of excitation frequency and amplitude ratio. FIG.3 is a phase diagram that shows this relationship. This graph compares the effect of different normalized excitation amplitude ratios to a normalized excitation frequency. Here, 1.0 represents the resonant frequency for the fluid. The amplitude ratio reflects the amplitude of the created sloshing wave relative to a length scale proportional to the cross-sectional long-axis internal dimension. There are three primary regimes of physical behavior when we drive the fluid at different frequencies and different amplitudes. This bifurcation diagram can be obtained using Miles weakly nonlinear wave theory, which is applicable unless the forcing amplitude is very large.

[0036] Where the driving frequency is substantially higher or lower than the resonant frequency the fluid acts in the planar wave regime. In this regime, little to no sloshing will occur, which prevents effective mixing. In the region near the resonant frequency and for higher amplitude ratios for low frequency, the fluid can either be in the swirling motion regime, which is largely stable, or in a chaotic sloshing regime. In the chaotic sloshing regime, the amplitude can grow over time. This can be problematic.

[0037] Embodiments aim to keep the action of the fluid within the stable swirling motion regime 10. This is the region for the most efficient mixing. Above another threshold, the fluid will be in a planar wave regime. To achieve efficient mixing, one should operate within the largely stable swirling regime or the chaotic sloshing mode regime. However, in the chaotic sloshing regime the sloshing amplitude can grow over time and cause fluid spatter or generate bubbles due to air entrainment as the free surface swells and rolls back over itself. Therefore, it is desirable to operate within the largely stable swirl regime. This can be accomplished by empirically pre-calibrating the input power levels as a function of reaction fluid volume and reaction fluid types. Such calibration of the input amplitude would also account for variations in the properties of the different reaction fluid types which can vary by intrinsic properties, such as density, viscosity, and nonlinear rheological properties.

[0038] By operating at or near resonance, a desirable sloshing modality can be achieved using optimal power input to the transducer while yielding the strongest coupling between acoustic energy input and the resulting mixing performance. This performance is achieved through the induced bulk convection in the fluid volume in the form of internal circulation that the stable swirl induces. An additional benefit of controlled operation at or near this sloshing resonance is that the excitation / relaxation process of the sloshing motion limits the deformation of the free surface and rollback on itself. This tends to induce less air entrainment and therefore the possibility of bubble generation and / or frothing (in the case of certain fluid types / reagents) is reduced. These bubbles can be an undesirable side effect of mixing that may be detrimental to photometric analysis results.

[0039] In an exemplary embodiment, a test was performed using a 25 microliter sample (having a 7.4 cPoise viscosity) and 95 ul of reagent (water). The transducer used has a 1.6 MHz narrow-bandwidth ultrasonic resonant frequency of the transducer. The transducer was pulsed with a square pulse with 40 msecs ON and 30 msecs OFF. Note, this is just one set of characterizations performed. Testing was also performed with a 70 msec pulse period with 40 msec ON and 30 msec OFF times that yielded further improved mixing performance. In oneexperiment, for a 240 µL fluid (215µL reagent + 25 µL sample), different periods with a 62.5% ON were tried.50-70 ms pulse periods were found to result in full mixing, while longer periods resulted in incomplete mixing. Full mixing was achieved within a predetermined mixing time of under a second (assessed through image analysis), or within seven cycles of the pulsed ultrasound waves. Other frequencies can be used depending on the resonant frequency of the exact cuvette being used.

[0040] As discussed earlier, embodiments utilize an ultrasonic beam that is angled upward from the side, towards the free surface of the fluid. Thus, the transducers involved in the ultrasonic waveform should be placed horizontally lower than the free surface and should be suitably oriented towards the free surface, such that the effective portion of the ultrasonic beam impinges on an optimal portion of the free surface. This may require adjustment of the beam incidence angle or change in the vertical placement of the beam source relative to the free surface for different fluid samples having different volumes. Exemplary prior art discloses horizontally oriented ultrasonic waves that are not angled toward the surface. Exemplary prior art requires repositioning the cuvette to place the ultrasonic elements near the height of the free surface for different fluid volumes or requires multiple separate transducers that are selected based on the free surface height.

[0041] Rather than selectively activating a single ultrasonic element, some embodiments utilize active beam steering and focusing using a phased array. An exemplary phased array 20 is shown in FIG.4. In this example, four elements are shown, but any suitable number of ultrasonic elements can be used. Similarly, a larger phased array can comprise several elements, and a subset of these, such as the four shown can be active during a mixing process, while the others remain off. A relative phase delay can be added to individual elements from a single drive signal to selectively steer the angle of the beam emitted by the array (beam steering).

[0042] In an exemplary setup shown in FIG.4, each element has a 1-5 mm height 22, 1-5 mm width 24, and a 0.5 mm element separation gap between them. The distance 28 between the phased array center of the cuvette is 5-25 mm. This was found empirically to result in a good mix of intensity and the ability to steer the beam using the phased array. While four elements are illustrated, any suitable number of elements can be used; four elements are used for ease of illustration. Note that the dimensions used can vary the preferred beam angles substantially. For example, using a transducer to cuvette distance of 15 mm and an exemplary cuvette geometry, changing the fluid volume from 80 ml to 240 ML volume (correspondingto a height of 4 mm and 10 mm) changes the preferred beam steering angle between 5° and 23°. While a shorter distance between the transducers and the cuvette can impart greater acoustic pressure on the free surface and hence induce larger degree of sloshing, steeper beam angles would be needed for smaller transducer-cuvette distance. In another exemplary setup for array 20, element height is 2.5 mm and 1.5 mm in another; width 24 is 2 mm and 3 mm in another. The separating gap can also vary by embodiment. The exact size of each element varies in different embodiments depending on the number of elements in the array, the mean angle of the array relative to the cuvette, the size of the cuvette, the distance from the cuvette, etc. In some embodiments, the individual elements have a uniform size, while in others the individual elements vary in size. For example, an array can include a combination of larger and smaller elements to help shape the ultrasonic wavefront for the application. While some embodiments have been found to work best with an incident beam angle to the free surface of 3-30 degrees, sloshing is often optimal when the incidence is below 30 degrees.

[0043] Given the acoustic impedance mismatch between air and water, near-total internal reflection is achieved at a wide range of incident beam angles at the water-air interface. A minimum angle condition (from horizontal) comes from the fact that we want to ensure a positive beam angle (directed upwards) in the presence of transducer and cuvette assembly tolerances. Further, a lower beam angle implies a higher location of the transducer which would be constrained by the need to have the transducer immersed within the water bath. A larger beam incidence angle allows for the transducer to be lowered relative to the bath waterline thus ensuring the transducer is fully submerged in the water bath. On the other hand, a lower incidence angle results in the reflected pressure wave exerting more of a sideways force on the free surface thus primarily exciting the asymmetric sloshing mode (desired). Steeper (larger) incidence angles tend to excite in larger measure the symmetric sloshing mode that can result in splashing of the fluid mixture. Accordingly, some embodiments use a beam angle from the array upward relative to the horizontal plane of between 3° and 30°.

[0044] In some embodiments, multiple four-element sub-arrays can be selectively used for fluids of different heights. This allows a desirable beam incidence angle of less than 10° on the free surface air / fluid boundary 26 using a 25 mm beam length. Some embodiments utilize a five or six-element array. The size and placement of these elements can beconstrained by the water line of the temperature control bath and the vertical placement of the free surface.

[0045] When the ultrasonic beam impinges free surface 26, it creates a pressure that causes the surface to deform and swell, resulting in surface 26a. When the beam is modulated in accordance with the resonant frequency of the surface, surface 26a sloshes in a harmonic fashion. For sufficiently large amplitude of the input, the motion causes a swirling motion 30 in the bulk of the fluid.

[0046] FIG.5 shows exemplary results of beam steering using a phased array approach. In these plots, the height of the ultrasound beam in the cuvette is shown vertically. The horizontal axis is across the beam (into the page with respect to FIG.4). As can be seen in these plots, different vertical angles / shifts can be achieved using the phased array with a resulting focused beam that has the desired beam cross-section (sufficiently large beam width and height). In the final plot, with the steepest angle and largest resulting translation of the beam axis along the vertical cuvette axis, the beam cross-sectional profile includes artifacts. Therefore, this exemplary phased array can be used to steer the beam angle such that the center of the beam can be moved cleanly up to 3.5 mm within the cuvette fluid before the beam loses collimation. Accordingly, 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. The distance that phased array can adjust before losing collimation varies depending on the specific geometry used for an embodiment. Alternatively, in some embodiments, a mechanical approach can be used to raise or lower a phased array relative to a cuvette or vice versa.

[0047] FIG.6 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 includefrequency, intensity, pulse width, height, and angle for the beam, 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 ultrasonic emissions. 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.

[0048] Selecting the elements gives the elevation (vertical offset relative to cuvette bottom) of the beam source, while choosing the phase between signals determines angle and where the beam impinges the free surface (at rest). In this manner, the exact location and orientation of the beam incidence on the fluid free surface can be selected. For exemplary piezoelectric elements for use with some embodiments, a 1.6 MHz primary drive waveform is used. A high-frequency signal is modulated, such as by pulse width modulation, by the driver circuit 56 to pulse the ultrasonic beam at or near the resonant frequency for the fluid. For example, in some embodiments using the above-mentioned cuvette geometry, this pulse width frequency will be around 14.6 Hertz, depending on fluid height and other characteristics as determined by processor 52. This allows an ultrasonic pulsed beam 55 with the desired characteristics to be directed at free surface 61 of fluid 62 within cuvette 60. The phased array can have a fixed tilt relative to the vertical axis of the cuvette to account for a mean beam incidence angle across the range of fluid height, Active beam-steering can then additionally adjust the beam angle to within the desired optimal range across the full range of fluid column height. A phased array having a tilt of less than 15 degrees relative to a vertical plane is said to be substantially vertical. Modulating the pulses of the ultrasonic transmission is said to be substantially near the resonant frequency when the pulsing frequency is within 20% of the resonant frequency. In some embodiments, the phased array can have elements that are angled relative to one another, arranged in an arc rather than a plane, or phase shifted relative to one another to introduce a focus to the ultrasonic beam aimed near the free surface. In some embodiments, a planar arrangement is used to create a planar beam.

[0049] In some embodiments, driver 56 also selectively drives an additional transducer 64 that is positioned at the bottom of cuvette 60 and directed upward. This bottom transducer need not be physically separate from the vertical phased array and can be part of a single assembly, in some embodiments. In some embodiments, the bottom transducer is one or more elements of the phased array, placed substantially horizontally to face substantially verticallyunder the cuvette. In embodiments that use a bottom transducer, processor 52 has further control of how energy is injected into fluid 62. With the exemplary geometry, the resonant frequency (corresponding to the symmetric (0,0) sloshing mode along the height of the fluid column) of the fluid is between 9-10 Hz. However, experimental results have shown that better results can be achieved when the bottom transducer is driven with the same modulation frequency as a horizontally directed phased array. Therefore, some embodiments that use a bottom transducer also drive the bottom transducer with the same modulation frequency, but different pulse width and phase characteristics than a phased array beam. A small pulse-on overlap of the order of 45-120 deg equivalent phase between the bottom and side transducers was found to yield good mixing performance. Further, the pulse-width and phase characteristics as well as the duty-cycle of the pulse would determine the relaxation characteristics of the sloshing fluid which in turn, would determine mixing performance as well as the risk of forming bubbles of splashing of the sloshing fluid. These parameters are therefore, tuned carefully through characterization of mixing for various fluid types (assays).

[0050] Cuvette 60 is positioned in front of phased 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).

[0051] FIG.7 shows some exemplary waveforms that may be provided to the piezoelectric ultrasonic elements in FIG.6. Pulses 70 include pulse width modulated trains, such as 1.5MHz voltage signals that are modulated around 12-13 hertz to match the resonance of some geometries. Some geometries resonate better with a 1.2-2.0 MHz voltage signals that are modulated around 14-15 hertz. Signal 70 is provided to piezoelectric elements in phased array 58. This waveform is provided with a phase shift at the ultrasonic frequency to different elements in the array to create an angled beam. Waveform 72 is the driving signal provided to bottom transducer 64. It includes an ultrasonic signal at the resonant frequency of the transducer, such as in the MHz range. This signal is modulated at the same frequency as the phased array so that these ultrasonic pulses can be provided synchronously to cause the fluid to resonate in a swirling and sloshing manner. As can be seen in this example, the modulation for the bottom transducer is out of phase with the modulation for the phased array. The exact optimal phase shift and optimal relative duty cycle of these two drive signalscan be determined empirically for a given cuvette geometry. In experiments, it was found that mixing performance was best when the bottom transducer was driven roughly out of phase with the phased array, but with a small phase shift. That is, the vast majority of the pulsing of the bottom transducer occurs when the side transducer is off. A substantial portion of the bottom pulse (at least 60%) occurs when the side transducer is off.

[0052] FIGs.8a -8d show four different embodiments for ultrasonic mixing. In these embodiments, the phased array is shown as an angled rectangle to emphasize that the beam will be at a shallow angle to the free surface. The phased array need not be physically oriented at an angle to the cuvette. It can be aligned parallel to the cuvette wall (normal to the free surface at rest) and the selective phase delay between elements can produce the equivalent of a coplanar surface oriented at an angle. Similarly, the phased array can be angled or can include sub-arrays that are normal to the mean angle for which each sub-array will be used. In mixer 80 of FIG.8a, a single phased array 81 is used to direct an ultrasonic beam at the free surface of the fluid.

[0053] In each of the embodiments disclosed in FIGs.8a - 8d, the phased arrays ideally aim at the free surface such that the center of the beam impinges the free surface at a point between the center of the cuvette and the wall closest to the phased array. However, given that this is used in a high-speed environment using injection-molded, disposable cuvettes on a rotating platform, manufacturing and operational tolerances can limit the precision with which the beam is aimed at the free surface. Embodiments aim to have an ultrasonic beam between 5 and 10° that the center impinges the free surface between the center and the leading face of the cuvette. However, this may not always be possible during operation. Mixing tests have shown that the mixing techniques disclosed herein are still effective when the intersection of the center of the beam and the free surface is less than this ideal location.

[0054] FIG.8b shows an alternative embodiment of a mixer 82. Similar to embodiment 80 in FIG.8a a bottom transducer 83 is added. This can be a single transducer or a set of transducers similar to the phased array 81. In some embodiments, the driver is configured to operate transducer 83 as a phased array, aiming the resulting beam at the center of the free surface. Experiments using different bottom transducer embodiments reveal that mixing is most efficient in embodiments where the bottom transducer acts as a planar source having a center between the center of the cuvette and the plane of the phased array on the side. Ideally, this planar source should be angled such that the center of the beam impinges the free surfacenear the center of the free surface. That is, best mixing results can be found when the bottom transducer is slightly offset and angled, at least in some geometries.

[0055] FIGs.8c and 8d show embodiments (mixers 84 and 86) similar to those in FIGs. 8a and 8b, but with an additional phased array 85 on the other side of the cuvette. Phased arrays 81 and 85 can be modulated at the same frequency but out of phase with one another to enhance the sloshing mode of the fluid. In some embodiments, during the quiescent portion of the modulation, each phased array can be used to detect the ultrasonic radiation of the opposing phase array. 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.

[0056] FIG.8d shows a mixer 86 that is similar to mixer 82 in FIG.8b, but with two opposing horizontal phased arrays (81 and 85) and two bottom transducers (83 and 85). In some embodiments, a single bottom transducer is used in conjunction with two opposing horizontal phased arrays. These bottom transducers can supplement the swirling motion within the bulk of the fluid that is induced by the horizontal phased arrays.

[0057] FIGs.8e -8h show four examples for ultrasonic mixing with different phased array. FIGs.8e and 8f show operating examples of a system 90 having a planar phased array 92. In these examples, there is a natural angle of repose to phase array 92 that aims upwards. By selecting a subset of elements 92a and 92b, phased array 92 can aim at the different free surface levels within cuvette 60 to induce a mixing mode described throughout. By selecting the uppermost elements 92a, the phased array can aim at free surfaces at levels 94 and 94a without losing collimation. When elements 92a are operated in phase, beam 93 aims at free surface level 94. By operating these elements with a slight phase shift, the beam direction 93a can aim at a higher surface level 94a, by steering the beam a few degrees upwards. Similarly, by selecting the lower elements 92b, the beam can be steered to aim at lower heights of free surfaces without losing collimation. When elements 92b are operated in phase, beam 93c aims at free surface level 94c. By operating these elements with a slight phase shift, the beam direction 93d can aim at a higher surface level 94d, by steering the beam a few degrees upwards.

[0058] FIGs.8g and 8h show operating examples of a system 90a having a concave phased array 95. This can improve focusing of the beam on the free surface. In these examples, there is a natural angle of repose to phase array 95 that aims upwards. By selecting a subset of elements 95a and 95b, phased array 95 can aim at the different free surface levels within cuvette 60 to induce a mixing mode described throughout. By selecting the uppermost elements 95a, the phased array can aim at free surfaces at levels 94e and 94f without losing focus. When elements 95a are operated in phase, beam 93e aims at free surface level 94e. By operating these elements with a slight phase shift, the beam direction 93f can aim at a higher surface level 94f, by steering the beam a few degrees upwards. Similarly, by selecting the lower elements 95b, the beam can be steered to aim at lower heights of free surfaces without losing collimation. When elements 95b are operated in phase, beam 93g aims at free surface level 94g. By operating these elements with a slight phase shift (time delay), the beam direction 93h can aim at a higher surface level 94g, by steering the beam a few degrees upwards. It should be noted that the elements in FIGs.8e-8h are not necessarily to scale and that they extend the width of the cuvette or more into the page. Additionally, in some embodiments, element size is non-uniform, including elements of different heights. For example, the lower-most element in group 92b and 95b can be much taller than the other elements, in some embodiments.

[0059] 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 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 phased array so that it can be aimed at the free surface.

[0060] At step 106, the processor determines the ideal ultrasonic beam characteristics that will be applied to the fluid contents of the cuvette for each phased array and bottom transducer. This includes selecting the piezoelectric elements of the phased array(s) that will be activated, as well as the phase delay between elements to direct the beam (or the requiredangle, where the driver is capable of determining the specific delays). This can also include the intensity / amplitude of the driving signal, the frequency of the modulation of the ultrasonic excitation, pulse type, and on / off times or duty cycles to be used to mix the fluid in the stable- swirl mode sloshing regime. The processor can determine these parameters using information about the volume and the intrinsic properties, as discussed throughout. At step 108, the processor provides this information to the driver circuit.110, the driver circuit operates the phased array(s) to emit a beam through the side(s) of the cuvette using beam steering. The driver creates driving waveforms that will be applied to the piezoelectric elements in the phased 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 to produce pulses at or near the resonant frequency of the fluid. The driver uses the parameters received at step 108 to control the operation of the ultrasonic elements to modulate the ultrasonic transmission at the fundamental asymmetric sloshing mode resonant frequency of the fluid.

[0061] At step 112, the ultrasonic beam(s) created by the piezoelectric elements reaches the fluid, provides driving forces on the free surface, and in turn, induces a swirling motion within the bulk of the fluid while the free surface moves in a sloshing manner. After several pulses of 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 within fewer than 8-10 pulses. In some embodiments, only pulses are provided, allowing the fluid to be completely mixed in ~0.5 seconds. 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 for half a second before moving again. This allows very high throughput for a mixing station within the CC analyzer.

[0062] 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.

[0063] Clinical Chemistry Analyzer Module

[0064] 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 with 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 laboratory automation system (LAS) interface module. The MVCC communicates with an LIS to gather and report status of patient samples as they are processed.

[0065] 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 exemplary 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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 anenvironmentally / 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.

[0071] 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).

[0072] 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).

[0073] 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.

[0074] 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 drawn 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.

[0075] 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 isdelivered 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.

[0076] 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 when 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.

[0077] 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.

[0078] 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 thepipette 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.

[0079] 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.

[0080] 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.

[0081] 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 metering system.

[0082] 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.

[0083] 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 drawn 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.

[0084] 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.

[0085] 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 allow 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.

[0086] The primary function of reagent arms 342 and 344 is to move aliquots of reagents from reagent server 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 will 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.

[0087] 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.

[0088] 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.

[0089] The assay is initiated with addition of the first reagent (R1) 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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 identify the cartridge (reagent manual load station 356). Reagent loader 354 then places the cartridge in the appropriate server position (in server 345 or 346).

[0095] 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.

[0096] 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 openedin 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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 customary practice in the art to which these teachings pertain.

[0103] 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 which are explicitly contemplated herein.

[0104] 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 flowchart illustrations and / or block diagrams, and combinations of blocks in the flowchart illustrations and / or block diagrams, can be implemented by computer readable program instructions.

[0105] 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 computerreadable 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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 willbe 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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 notbe 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 system 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.”

[0114] 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.

[0115] 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. 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

[0116] The following is a list of non-limiting illustrative embodiments disclosed herein:

[0117] Illustrative embodiment 1. A liquid mixing system comprising: a cuvette configured to hold a fluid to be mixed; a first phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a first ultrasonic transmission through a first face of the cuvette at an upward angle that is within a range of beam-incidence of 3 to 30 degrees; and a driver circuit configured to control the operation of the ultrasonic elements and to modulate the first ultrasonic transmission substantially at an asymmetric sloshing mode resonant frequency of the fluid.

[0118] Illustrative embodiment 2. The liquid mixing system according to the preceding embodiment, wherein the first phased array is concave.

[0119] Illustrative embodiment 3. The liquid mixing system according to one of the preceding embodiments, wherein the driver circuit modulates the first ultrasonic transmission at a rate that is substantially at a frequency defined by sqrt((g / 2 / pi)*(tanh(pi*h / l)) / l), where g is gravity, h is fluid height, and l is the length of the cuvette in the direction of the first ultrasonic transmission.

[0120] Illustrative embodiment 4. The liquid mixing system according to one of the preceding embodiments, further comprising a processor configured to select modulation properties of the first ultrasonic transmission based on at least a volume of the fluid.

[0121] Illustrative embodiment 5. The liquid mixing system according to one of the preceding embodiments, further comprising a processor configured to select modulation properties comprising excitation amplitude, modulation frequency, pulse-type, and pulse duty-cycle such that the fluid is mixed in a stable swirl sloshing regime.

[0122] Illustrative embodiment 6. The liquid mixing system according to one of the preceding embodiments, further comprising a second phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a second ultrasonic transmission through a second face of the cuvette, opposite to the first face.

[0123] Illustrative embodiment 7. The liquid mixing system according to one of the preceding embodiments, wherein the driver circuit is configured to pulse the second phased array out of phase with the first phased array at the resonant frequency of the fluid.

[0124] Illustrative embodiment 8. The liquid mixing system according to one of the preceding embodiments, further comprising a bottom ultrasonic transducer placed below the cuvette and configured to emit a second ultrasonic transmission through the bottom of the cuvette towards the free surface of the fluid, substantially modulated at the resonant frequency.

[0125] Illustrative embodiment 9. The liquid mixing system according to one of the preceding embodiments, wherein the bottom ultrasonic transducer is operated out of phase with the first phased array such that a substantial part of a pulse by the bottom ultrasonic transducer occurs between pulses by the first phased array.

[0126] Illustrative embodiment 10. A method of operating a liquid mixing system comprising: placing a cuvette holding a fluid to be mixed in front of a first phased array of ultrasonic elements oriented in a substantially vertical array; operating the first phased array to emit a first ultrasonic transmission, using beam steering, through a first face of the cuvette at an upward angle that is within a range of beam-incidence of 3 to 30 degrees; and controlling the operation of the ultrasonic elements to modulate the first ultrasonic transmission substantially at a fundamental asymmetric sloshing mode resonant frequency of the fluid.

[0127] Illustrative embodiment 11. The method according to the preceding embodiment, further comprising selecting, using a processor, modulation properties of the first ultrasonic transmission based on at least a volume of the fluid.

[0128] Illustrative embodiment 12. The method according to one of the preceding embodiments, further comprising selecting, using a processor, modulation properties of the first ultrasonic transmission based on at least one intrinsic property of the fluid.

[0129] Illustrative embodiment 13. The method according to one of the preceding embodiments, further comprising selecting, using a processor, modulation properties comprising excitation amplitude, modulation frequency, pulse type, and pulse duty-cycle such that the fluid is mixed in a stable-swirl mode sloshing regime.

[0130] Illustrative embodiment 14. The method according to one of the preceding embodiments, further comprising operating a second phased array of ultrasonic elements oriented in a substantially vertical array to emit a second ultrasonic transmission through a second face of the cuvette, opposite to the first face.

[0131] Illustrative embodiment 15. The method according to one of the preceding embodiments, further comprising pulsing the second phased array out of phase with the first phased array at the fundamental asymmetric sloshing-mode resonant frequency of the fluid.

[0132] Illustrative embodiment 16. The method according to one of the preceding embodiments, further comprising operating a bottom ultrasonic transducer placed below the cuvette to emit a second ultrasonic transmission through the bottom of the cuvette towards the free surface of the fluid, substantially modulated at the sloshing mode resonant frequency.

[0133] Illustrative embodiment 17. A liquid mixing system comprising: a ring configured to hold and move a plurality of reaction vessels containing fluid comprising a patient sample and reagent to be mixed; a first phased array of ultrasonic elements oriented in a substantially vertical array configured to emit a first ultrasonic transmission through a first face of each reaction vessel when placed by the ring at a position proximate to the first phased array at an upward angle such that the first ultrasonic transmission intersects a free surface of the fluid; and a driver circuit configured to control the operation of the ultrasonic elements and to modulate the first ultrasonic transmission substantially at a fundamental asymmetric sloshing resonant frequency of the fluid.

[0134] Illustrative embodiment 18. The liquid mixing system according to the preceding embodiment, further comprising a second phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a second ultrasonic transmission through a second face of each reaction vessel opposite to the first face.

[0135] Illustrative embodiment 19. The liquid mixing system according to one of the preceding embodiments, further comprising a bottom ultrasonic transducer placed below the reaction vessel and configured to emit a second ultrasonic transmission through the bottom of the reaction vessel towards the free surface of the fluid, substantially modulated at the sloshing mode resonant frequency.

[0136] Illustrative embodiment 20. The liquid mixing system according to one of the preceding embodiments, further comprising a processor configured to select modulation properties comprising excitation amplitude, modulation frequency, pulse type and pulse duty- cycle such that the fluid is mixed in a stable-swirl mode sloshing regime.

[0137] Illustrative embodiment 21. The liquid mixing system according to one of the preceding embodiments, wherein the upward angle is within a range of beam-incidence of 3 to 30 degrees relative to horizontal.

[0138] Illustrative embodiment 22. The liquid mixing system according to one of the preceding embodiments, wherein the second phased array monitors the performance of the first phased array.

Claims

CLAIMS We claim:

1. A liquid mixing system comprising: a cuvette configured to hold a fluid to be mixed; a first phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a first ultrasonic transmission through a first face of the cuvette at an upward angle that is within a range of beam-incidence of 3 to 30 degrees; and a driver circuit configured to control the operation of the ultrasonic elements and to modulate the first ultrasonic transmission substantially at an asymmetric sloshing mode resonant frequency of the fluid.

2. The liquid mixing system of claim 1, wherein the first phased array is concave.

3. The liquid mixing system of claim 1, wherein the driver circuit modulates the first ultrasonic transmission at a rate that is substantially at a frequency defined by sqrt((g / 2 / pi)*(tanh(pi*h / l)) / l), where g is gravity, h is fluid height, and l is the length of the cuvette in the direction of the first ultrasonic transmission.

4. The liquid mixing system of claim 1, further comprising a processor configured to select modulation properties of the first ultrasonic transmission based on at least a volume of the fluid.

5. The liquid mixing system of claim 1, further comprising a processor configured to select modulation properties comprising excitation amplitude, modulation frequency, pulse- type, and pulse duty-cycle such that the fluid is mixed in a stable swirl sloshing regime.

6. The liquid mixing system of claim 1, further comprising a second phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a second ultrasonic transmission through a second face of the cuvette, opposite to the first face.

7. The liquid mixing system of claim 6, wherein the driver circuit is configured to pulse the second phased array out of phase with the first phased array at the resonant frequency of the fluid.

8. The liquid mixing system of claim 1, further comprising a bottom ultrasonic transducer placed below the cuvette and configured to emit a second ultrasonic transmissionthrough the bottom of the cuvette towards the free surface of the fluid, substantially modulated at the resonant frequency.

9. The liquid mixing system of claim 8, wherein the bottom ultrasonic transducer is operated out of phase with the first phased array such that a substantial part of a pulse by the bottom ultrasonic transducer occurs between pulses by the first phased array.

10. A method of operating a liquid mixing system comprising: placing a cuvette holding a fluid to be mixed in front of a first phased array of ultrasonic elements oriented in a substantially vertical array; operating the first phased array to emit a first ultrasonic transmission, using beam steering, through a first face of the cuvette at an upward angle that is within a range of beam-incidence of 3 to 30 degrees; and controlling the operation of the ultrasonic elements to modulate the first ultrasonic transmission substantially at a fundamental asymmetric sloshing mode resonant frequency of the fluid.

11. The method of claim 10, further comprising selecting, using a processor, modulation properties of the first ultrasonic transmission based on at least a volume of the fluid.

12. The method of claim 10, further comprising selecting, using a processor, modulation properties of the first ultrasonic transmission based on at least one intrinsic property of the fluid.

13. The method of claim 10, further comprising selecting, using a processor, modulation properties comprising excitation amplitude, modulation frequency, pulse type, and pulse duty-cycle such that the fluid is mixed in a stable-swirl mode sloshing regime.

14. The method of claim 10, further comprising operating a second phased array of ultrasonic elements oriented in a substantially vertical array to emit a second ultrasonic transmission through a second face of the cuvette, opposite to the first face.

15. The method of claim 14, further comprising pulsing the second phased array out of phase with the first phased array at the fundamental asymmetric sloshing-mode resonant frequency of the fluid.

16. The method of claim 10, further comprising operating a bottom ultrasonic transducer placed below the cuvette to emit a second ultrasonic transmission through the bottom of the cuvette towards the free surface of the fluid, substantially modulated at the sloshing mode resonant frequency.

17. A liquid mixing system comprising: a ring configured to hold and move a plurality of reaction vessels containing fluid comprising a patient sample and reagent to be mixed; a first phased array of ultrasonic elements oriented in a substantially vertical array configured to emit a first ultrasonic transmission through a first face of each reaction vessel when placed by the ring at a position proximate to the first phased array at an upward angle such that the first ultrasonic transmission intersects a free surface of the fluid; and a driver circuit configured to control the operation of the ultrasonic elements and to modulate the first ultrasonic transmission substantially at a fundamental asymmetric sloshing resonant frequency of the fluid.

18. The liquid mixing system of claim 17, further comprising a second phased array of ultrasonic elements oriented in a substantially vertical array and configured to emit a second ultrasonic transmission through a second face of each reaction vessel opposite to the first face.

19. The liquid mixing system of claim 17, further comprising a bottom ultrasonic transducer placed below the reaction vessel and configured to emit a second ultrasonic transmission through the bottom of the reaction vessel towards the free surface of the fluid, substantially modulated at the sloshing mode resonant frequency.

20. The liquid mixing system of claim 17, further comprising a processor configured to select modulation properties comprising excitation amplitude, modulation frequency, pulse type and pulse duty-cycle such that the fluid is mixed in a stable-swirl mode sloshing regime.

21. The liquid mixing system of claim 17, wherein the upward angle is within a range of beam-incidence of 3 to 30 degrees relative to horizontal.

22. The liquid mixing system of claim 18, wherein the second phased array monitors the performance of the first phased array.

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