WO2006105616A1 - Method for microfluidic mixing and mixing device - Google Patents
Method for microfluidic mixing and mixing device Download PDFInfo
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- WO2006105616A1 WO2006105616A1 PCT/AU2006/000473 AU2006000473W WO2006105616A1 WO 2006105616 A1 WO2006105616 A1 WO 2006105616A1 AU 2006000473 W AU2006000473 W AU 2006000473W WO 2006105616 A1 WO2006105616 A1 WO 2006105616A1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
- B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
- B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
- B01F31/86—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations with vibration of the receptacle or part of it
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00479—Means for mixing reactants or products in the reaction vessels
- B01J2219/00484—Means for mixing reactants or products in the reaction vessels by shaking, vibrating or oscillating of the reaction vessels
- B01J2219/00486—Means for mixing reactants or products in the reaction vessels by shaking, vibrating or oscillating of the reaction vessels by sonication or ultrasonication
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00889—Mixing
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
- B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
Definitions
- This invention relates to microfluidic mixing.
- New-generation pathology-testing devices are examples of microtechnological systems where small quantities (nanolitres) of liquid need to be mixed.
- small quantities nanolitres
- millilitres volume of a patient's body fluids
- reagents indicating particular medical conditions.
- This causes significant delays between test and diagnosis.
- At least the part of the device in contact with the sample should be disposable to eliminate expensive sterilization and cross-contamination issues, and micro-volumes allow cheap, disposable sample-processing elements.
- one or more microlitre-sized drops must be mixed.
- detection of a target molecule relies on target molecules in the liquid being driven on a sufficiently space-filling trajectory for it to contact to the detector surface in as short a time as possible. In such 'batch' processes, most typical of pathology tests, engineering of complex devices to pump or stir the liquids together could make the device uneconomic.
- An application typical of the new generation of screening-type pathology tests is to mix a single drop of patient's sample fluid with a pre-loaded 'reagent' or detector liquid, which would most probably contain engineered antibodies used in an immunoassay.
- the sample could be taken from a pinprick or swab, and might be collected in a context such as an airport, or a patient's point-of-care, where an elementary 'maybe/no' screening result is needed in a short time.
- the mixing should occur on a 'chip' that is simple and cheap enough to be disposable, so that any complex electronics are housed in a separate, 'reader' unit.
- the antibodies would bind to it and undergo a colour or fluorescence change, or cause an optical change in the properties of the surface to which antibodies may be bound. This change would be detected by equipment in the reader unit.
- the challenge is to design a chip that is capable of receiving a single drop, without a complex liquid feeding system, and mix the drop efficiently enough with the reagent for any binding reactions to occur over a timescale of tens of seconds rather than hours. Timescales of hours would render the test useless from a point-of-care perspective.
- Acoustic microstreaming is a phenomenon where sound waves propagating around a small object create a mean flow in the vicinity of the obstacle. It is a nonlinear second-order effect driven by the viscous shear in the boundary layer near the object. It is particularly enhanced where the object is a bubble, because the bubble can resonate to the applied sound in one or more ways, locally amplifying and transforming the microstreaming effect. Bubbles can oscillate in several ways, the most common being a volumetric or 'breathing' mode 10 , which has a well-known natural frequency inversely proportional to the bubble radius. However, bubbles in microdevices are invariably near at least one wall, which is known to make a significant change to the volumetric mode frequency 11 .
- Liu et al. 3 ' 16 showed that acoustic microstreaming could be used for micromixing.
- air bubbles trapped in pockets inside a circular chamber 300 ⁇ m deep and 15 mm in diameter were excited; dye was used to observe the resulting streaming motion.
- dye was used to observe the resulting streaming motion.
- there is little quantitative information available about the flow field induced by the streaming and mixing times were subjectively estimated.
- US 2003/0175947 discloses a device which utilises one or more bubbles caused to oscillate at a resonant frequency in order to facilitate mixing by a process of cavitation microstreaming.
- the principle theory presented is that the microstreaming occurs when the relevant bubble undergoes volume change within a sound field.
- the teaching of the reference is that microstreaming, arising about a single bubble excited close to resonance, produces strong liquid circulation flow in the associated microfluidic chamber but that a variation in frequency or radius of the bubble from the conditions for maximum motion causes the streaming to be inappreciable.
- a method of mixing including: providing a first fluid in a well so as to establish an acoustic field gradient; and applying an acoustic signal to cause mixing within a fluid.
- the method further includes applying a second acoustic signal to effect chaotic mixing within the first fluid.
- the first and second signals are at first and second frequencies, respectively, for establishing flow patterns with streamlines that cross when the frequencies are alternately applied.
- the acoustic field gradient is formed between a first fluid and a second fluid.
- the first fluid is a liquid and the second fluid is a gas.
- the second fluid is in the form of a gas bubble within the first fluid.
- the second fluid is ambient air
- the first fluid contacts a wall of the well and the acoustic field gradient is established adjacent the wall.
- the contact of the fluid with the wall forms a meniscus, which produces the acoustic field gradient.
- a mixing device including a well for receiving a fluid to establish an acoustic field gradient, and an acoustic transmitter adapted to apply an acoustic signal to cause mixing within the fluid.
- the well is open to ambient air.
- a method of mixing including forming a bubble within a fluid and applying different acoustic frequencies such that the bubble adopts different modes of oscillation that drive different streaming patterns.
- the acoustic frequencies are applied such that transition of the bubble-driven flow between the different streaming patterns causes chaotic mixing of the fluid.
- the different frequencies cause the bubble to transition between one or more of linear translation, volume, shape, elliptical or circular orbiting oscillation modes.
- a mixing device including a housing which defines a chamber and provides a site for at least one bubble to be formed, and an acoustic transmitter adapted to apply the different frequencies.
- Figure 1 is a diagrammatic perspective view of a mixing device (equivalent to Figure
- Figure 2 is a perspective view of a bubble formed in the mixing device (also shown as
- Figure 3 illustrates streaming patterns around a bubble at various driving frequencies (also shown as Figure 5.7 in Annex A);
- Figure 4 is a diagrammatic view of an alternative mixing device
- Figure 5 is a plan view of a mixing chamber of the device of Figure 4.
- Figure 6 shows a time sequence of the mixing chamber, illustrating a diffusion process
- Figure 7 illustrates a longer time sequence of the diffusion process
- Figure 8 shows a time sequence of the mixing chamber with an applied frequency of 140
- Figure 9 shows a time sequence of the mixing chamber with an applied frequency of 195
- Figure 10 shows a time sequence of the mixing chamber, illustrating chaotic mixing.
- FIG. 1 An example of a mixing device 10 is shown in Figure 1 as including an acrylic housing 1 with an internal rectangular chamber 2 with a length and width dimension in the order of 30 mm and a depth dimension in the order of 0.66 mm.
- the chamber 2 provides a site for formation of a bubble 3 which is held captive on a wall 4 of a chamber 2.
- An acoustic transmitter 5 in the form of a piezoelectric disc 6 is also provided for transmitting acoustic waves through fluid within the chamber 3, for the purpose of generating oscillation modes of the bubble 3.
- the distance of the bubble 3 from the centre of the piezoelectric disc 6 may be in the order of 10mm.
- a microscope objective 7 is also provided for the purpose of observing the flow field around the bubble 3 during oscillation. Such observation allows experimental measurements to be carried out under a micro-particle image velocimetry (PIV) system, as well as streak photographs to be taken, for the purpose of determining velocity and fields of measurements of the motion of the bubble.
- PIV micro-particle image velocimetry
- the fluid within the cavity is provided with fluorescent microspheres or other suitable tracer particles.
- FIG. 3 shows streaming patterns around a 272 ⁇ m radius captive bubble at different driving frequencies. The majority of the streaming patterns shown exhibit some regularity or symmetry.
- Figure 3(a) shows a uniform circulation around the bubble, which resembles a potential vortex.
- Figure 3(b) shows a streaming pattern consisting of vortices split into four quadrants. This pattern is usually associated with a linear translating oscillation mode and will be referred to as a 'quadrupole' pattern for convenience.
- Figures 3(c) and 3(e) show streaming patterns with a plane of symmetry along the bubble with flow recirculating within each half. These patteras resemble a 'dipole'.
- Figure 3(f) shows the streaming pattern around a bubble that is undergoing a shape oscillation at 11 kHz. Not all the streaming patterns are symmetrical. As the frequency is varied, the streaming patterns undergo slight variations as they transform from one pattern to another. In these intermediate stages where the gradual changes occur, the pattern may not be symmetrical. An example of this is shown in Figure 3(d).
- the variation in streaming patterns with the driving frequency usually occurs continuously and smoothly. However, occasionally a sudden change in streaming pattern would occur. These would appear as either a reversal in flow direction or the sudden onset of a completely new mode of streaming such as when a bubble suddenly exhibits a shape oscillation.
- the sudden changes in streaming pattern may be the result of a resonance of the bubble or in the piezoelectric driving system. Resonances in the piezoelectric disk are demonstrated in Tho 12 , Section 3.2.1 where a plot of sound pressure against frequency showed numerous peaks in pressure amplitude.
- the variations in streaming pattern must be associated with different modes of oscillation of the bubble.
- Symmetrical streaming patterns are caused by symmetrical modes of oscillation of the bubble and likewise asymmetric streaming patterns must be a result of asymmetric modes of oscillation.
- the steadiness of the streaming suggests that whether or not the mode of oscillation is symmetric or asymmetric, it is at the very least periodic, otherwise the streaming velocities would fluctuate with time.
- the individual streaming patterns are investigated in Tho 12 , which is incorporated herein in its entirety. It is found the various patterns in fact result from the bubble adopting different oscillation modes as a result of the applied frequency. These modes can be broadly divided into translating modes of oscillation where the centroid of the bubble shifts in position; volume oscillations where the bubble expands and contracts in shape and volume, and shape oscillations where the surface of the bubble deforms into a variety of shapes.
- the measurements taken for all these modes of oscillation, with the exception of the shape mode oscillations, include streak photographs, micro-PIV determined velocity and vorticity fields and measurements of the motion of the bubble's centroid and radius.
- the streaming flows were shown to be affected by three main parameters: the excitation frequency, the pressure amplitude (a function of the voltage amplitude of the input signal) and the size of the bubble. Adjustment of the excitation frequency was shown to bring about the most significant changes in the streaming pattern.
- the streaming patterns mostly vary continuously and smoothly from one pattern to another as the frequency is varied. This gives rise to a wide variety of streaming patterns, some of which are regular and symmetrical.
- the variation in streaming pattern with the driving acoustic frequency has not been demonstrated before.
- the way in which the frequency alters the streaming pattern is believed to be a characteristic of the design and construction of the piezoelectric disk 6 and chamber 3, rather than an inherent frequency response in the bubble. The exception to this is when a bubble is forced into volume oscillations when it is excited at its natural resonance frequency.
- the microfluidic mixing device of the prior art utilised only the natural resonant frequency of the bubble as the driver for initiating cavitation microstreaming.
- the present invention takes advantage of a surprising result that the construction of the mixing device itself allows the bubble to adopt different modes of oscillation, which are also effective in generating cavitation microstreaming at frequencies other than the natural resonant frequency. Accordingly, when different frequencies are applied, the bubble will transition from one oscillating mode to another. During such transitions, streamlines within the velocity field surrounding the bubble will crossover. Crossing streamlines are known to generate chaotic flow which will substantially increase the mixing capability of the device far beyond that achieved using the microstreaming achieved with the prior art natural resonant frequency only.
- the set-up consists of a microscope 15 (World Precision Instruments PZMTIII) imaging the acoustic streaming experiment in standard transmission mode at 2x magnification.
- the light source was a tungsten lamp fed via a fibre-optic cable (Microlight 150 W).
- a digital camera 16 capable of 60 frames per second (Basler A602fc) was set at 7.5 frames per second.
- the white balance was set on background images and the gain and shutter speed were fixed during the experiments.
- the experimental mixing device 20 included a mixing chamber 21, which was made as simple as possible to illustrate the effects of chaotic acoustic micromixing relative to simple acoustic micromixing. However, future more complex designs affording better interfacial curvature via bubble trapping may be better.
- the chamber 21 was simply a 4 mm diameter hole drilled through an acrylic plate 22 76 x 195 mm in size and approx 1.63+/-0.02 mm thick, creating a cylindrical well 23.
- the chamber top 24 was open to the air and the bottom was sealed with office sticky tape 25 (Marbig clear).
- the apparent expediency of drilling only part-way through the plate to leave a solid acrylic bottom was eschewed, since experience showed that slight irregularities in the bottom surface properties would be harder to control, reducing experimental reproducibility.
- a function generator 27 (Wavetek model 145) was used to generate a sinusoidal signal with an amplitude of 1.00+/-0.02 V.
- the speaker volume control was set to maximum.
- a button microphone (Genexxa 33-3003) was mounted via a bubble-wrap vibration isolator on the acrylic plate.
- the microphone centerline was horizontal and on the well's horizontal centreline with an accuracy of +/-1 mm, and was about 13+/-1 mm above the plate top; the front of its face was 12+/-1 mm away from the well's vertical centreline.
- a standard foam windsock was fitted to the microphone.
- the microphone output showed several frequencies as well as the main 140 Hz response.
- the output was 55 mV peak-to-peak (pp).
- the microphone output was equally polyphonic and generated a spike at the main 195 Hz response that was 73 mV p-p, although most of the waveform power was about 55 mV p-p, as in the 140 Hz case.
- the pre-loaded 'reagent' or detector liquid was modelled by making a solution of 50 mL of glycerol (molecular weight 92.0) and 10 mL of de-ionized (DI) water into which had been dissolved 4 g of KCl. It was important to create a concave meniscus in the well, essentially because it permitted visualization of the entire chamber. If the meniscus were convex, it would act like a converging lens, creating a bright spot in the chamber centre surrounded by a wide black rim that would obscure most of the behaviour. Approximately 16 ⁇ L of the glycerol solution was placed in the well with a precision micropipette (Eppendorf lO ⁇ L).
- Blue dye was made by dissolving 2.523 g of Brilliant Blue dye (Asia Pacific Specialty Chemicals Limited, CI 42090, molecular weight 792.86) in 300 mL DI water. To begin the experiment, the dye was formed into a 0.100+/-0.005 ⁇ L drop and placed in the chamber. On the images to be shown, the initial drop size appears to vary somewhat, but this was due to small variations in the time taken to switch on the sound, plus the fact that the drop initially spreads rapidly on the surface only, as will be discussed shortly. Experiments were run with diffusion only, at two constant frequencies to be discussed shortly that both generated vigorous and different streaming patterns, and in a regime that alternated between the patterns.
- the images were stored as individual, uncompressed frames and transferred to a Unix computer for subsequent processing. Images were cropped to the well outline; and two alternative techniques of emphasizing any unmixed regions were applied. Firstly, a sequence of frames was composited together and a uniform gamma correction of 2.0 was applied to the composite image. This effectively brightened the image, stretching contrast in the dark dyed zones. Secondly, a standard histogram-equalization algorithm (Image Magick 5.4.7) was run on each frame to normalize the contrast between mixed and unmixed zones, and the resulting frames composited together.
- Figuer 8 shows the time sequence with an introduced sample drop under the influence of a constant-frequency acoustic micromixing regime at 140 Hz.
- Dark crescent-shaped regions on every frame are optical effects due to surface curvature.
- a gamma factor of 2.0 has been applied to the composite image in the top panel and in the bottom panel each individual frame has been histogram- equalized to emphasize any unmixed zones.
- Figure 9 shows the time sequence with an introduced sample drop under the influence of a constant-frequency acoustic micromixing regime at 195 Hz.
- Dark crescent-shaped regions on every frame are optical effects due to surface curvature.
- a gamma factor of 2.0 has been applied to the composite image in the top panel and in the bottom panel each individual frame has been histogram- equalized to emphasize any unmixed zones.
- Figure 10 shows the time sequence with an introduced sample drop under the influence of a chaotic acoustic micromixing regime cycling 15 s at 195 Hz, then 50 s at 140 Hz.
- Dark crescent-shaped region on every frame is an optical effect due to surface curvature.
- a gamma factor of 2.0 has been applied to the composite image in the top panel and in the bottom panel each individual frame has been histogram-equalized to emphasize any unmixed zones.
- FIG. 6 A typical situation after 210 s is shown in Fig. 6; here, the bulk of the introduced molecules would not have reached the bottom of the well yet. Experiments with this combination of liquids typically take well over an hour before the dye appears uniform. The diffusive behaviour over 50 min is shown in Fig. 7. Even after 50 min, diffusive instabilities have clearly not yet distributed the introduced molecules throughout the well, and a rough assessment of the mixing time would be at least 100 min.
- the application of an acoustic signal significantly enhances mixing, which results from microstreaming.
- the generation of acoustic microstreaming is due to the nonlinearities in the fluid dynamics momentum equation that rectify the first-order oscillatory motion to a second-order mean flow.
- One way of making the nonlinearities locally large is to arrange a large gradient in the acoustic field. Since a gas such as air has an acoustic impedance three orders of magnitude smaller than that of either liquids or polymeric solids, a sharp change in the interface between a liquid and its gaseous boundary, giving a small radius of curvature and hence large nonlinearities, should be sufficient to generate acoustic microstreaming.
- the bubble systems hitherto investigated are but one special and highly effective example of this phenomenon however it is now shown similar results may be obtained using a simple meniscus. It may be advantageous to generate microstreaming without trapped bubbles because the chip would be simpler.
- the objective of the experiments reported here was to compare the relative mixing times of pure diffusion, microstreaming due to a single pattern, and chaotic microstreaming due to alternating patterns. Since a definitive relative comparison was sought, the priority was to get accurate relative data rather than data from an actual biochemical test, in which additional, harder-to-control factors might compromise accuracy.
- the present experiments were done by dye flow visualization. Plain dye diffusion in water is much faster than most of the biochemical reactions foreshadowed, and would have resulted in an experiment that took seconds rather than minutes, reducing the accuracy with which any improvements could be assessed.
- the dye diffusion was slowed down by adding potassium chloride to the water and the mixing slowed down by adding glycerol to increase the viscosity of the water.
- the volume to be mixed should be approximately 10-50 ⁇ L, since this is a drop size that might be practically obtained from a patient without complex liquid handling (either too small or too large a volume would pose problems).
- targets e.g. virions, or antibodies in seropositive patients
- typical calculations on the concentrations of targets coupled with likely detector sensitivities, converge on a value of about 10-50 ⁇ L.
- acoustic microstreaming results in a decrease in mixing time between one and two orders of magnitude. It was found that the key feature of the device permitting high- amplitude streaming should be an interface between liquid and air with a sharp gradient, and that the gradient due to the free-surface meniscus in a hydrophobic well could be sufficient. More generally though, a large gradient could be caused by any interface with a small radius of curvature between media that have a significant difference in acoustic impedence.
- Examples of media that have significant differences in acoustic impedence are a liquid and a gas (or a solid and a gas); and an example of an interface with a sharp radius of curvature is a bubble; although the meniscus in a small well seems to do as well.
- This contact time may be related to the dye mixing rate but is likely to be much longer, since the diffusivity of a large protein may be very significantly lower than the dye molecules; the Peclet number which for a fixed advective process is the inverse of the diffusivity, would be much higher for a real antibody-antigen interaction. It has been shown that as the Peclet number increases, the benefits of chaotic mixing increase 19 . Future experiments should seek to quantify the improvement conferred on actual biochemical assays, using similar quantitative measures.
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US11/910,420 US8449171B2 (en) | 2005-04-08 | 2006-04-07 | Method for microfluidic mixing and mixing device |
AU2006230821A AU2006230821B2 (en) | 2005-04-08 | 2006-04-07 | Method for microfluidic mixing and mixing device |
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DE102007020243A1 (en) * | 2007-04-24 | 2008-10-30 | INSTITUT FüR MIKROTECHNIK MAINZ GMBH | Acoustic mixing and / or conveying device and sample processing chip with such |
DE102007020243B4 (en) * | 2007-04-24 | 2009-02-26 | INSTITUT FüR MIKROTECHNIK MAINZ GMBH | Acoustic mixing and / or conveying device and sample processing chip with such |
US8764275B2 (en) | 2007-04-24 | 2014-07-01 | INSTITUT FüR MIKROTECHNIK MAINZ GMBH | Method for mixing and/or conveying, mixing and/or conveyance device, and sample processing chip comprising such as device |
WO2012097413A1 (en) * | 2011-01-19 | 2012-07-26 | Howard Florey Institute | A method and apparatus for mixing microliter fluid volumes by application of acoustic signals |
US10473665B2 (en) | 2012-04-16 | 2019-11-12 | Commonwealth Scientific And Industrial Research Organisation | Methods and systems for detecting an analyte or classifying a sample |
US11385234B2 (en) | 2012-04-16 | 2022-07-12 | Commonwealth Scientific And Industrial Research Organisation | Methods and systems for detecting an analyte or classifying a sample |
EP4180799A1 (en) | 2012-04-16 | 2023-05-17 | Commonwealth Scientific and Industrial Research Organisation | Methods and systems for detecting an analyte or classifying a sample |
US11952612B2 (en) | 2016-11-14 | 2024-04-09 | Commonwealth Scientific And Industrial Research Organisation | Protease sensor molecules |
US11662349B2 (en) | 2017-08-08 | 2023-05-30 | Commonwealth Scientific And Industrial Research Organisation | Carbohydrate sensors |
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